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2015v1.0
 Emery’s
ELEMENTS OF
MEDICAL GENETICS
This page intentionally left blank
Emery’s edition

Elements of 15
Medical Genetics
Peter D. Turnpenny BSc MB ChB FRCP FRCPCH FRCPath FHEA
Consultant Clinical Geneticist,
Royal Devon and Exeter NHS Foundation Trust,
and
Honorary Clinical Professor,
University of Exeter Medical School

Sian Ellard BSc PhD FRCPath

Consultant Clinical Molecular Geneticist,
Royal Devon and Exeter NHS Foundation Trust,
and
Professor of Molecular Genetics and Genomic Medicine,
University of Exeter Medical School

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Preface viii
Acknowledgments ix
Dedication x
1 The History and Impact of Genetics
in Medicine 1
Gregor Mendel and the Laws of Inheritance 1
DNA as the Basis of Inheritance 3
The Fruit Fly 4
The Origins of Medical Genetics 4
The Impact of Genetic Disease 6
Major New Developments 6
The Societal Impact of Advances in Genetics 8
SECTION A
THE SCIENTIFIC BASIS OF
HUMAN GENETICS
2 The Cellular and Molecular Basis
of Inheritance 9
The Cell 9
DNA: The Hereditary Material 9
Chromosome Structure 10
Types of DNA Sequence 11
Transcription 14
Translation 15
The Genetic Code 16
Regulation of Gene Expression 16
RNA-Directed DNA Synthesis 17
Mutations 17
Mutations and Mutagenesis 21
3 Chromosomes and Cell Division
Human Chromosomes 24
Methods of Chromosome Analysis 26
Molecular Cytogenetics 27
Chromosome Nomenclature 28
Cell Division 29
Gametogenesis 32
Chromosome Abnormalities 33
4 Finding the Cause of Monogenic Disorders
by Identifying Disease Genes 42
Position-Independent Identification of Human
Disease Genes 42
Positional Cloning 43
Contents
The Human Genome Project 44
Identifying the Genetic Etiology of Monogenic
Disorders by Next-Generation Sequencing 47
5 Laboratory Techniques for Diagnosis of
Monogenic Disorders 50
PCR (Polymerase Chain Reaction) 50
Application of DNA Sequence Polymorphisms 50
Nucleic Acid Hybridization Techniques 52
Mutation Detection 54
Sequencing-Based Methods 57
Dosage Analysis 60
Towards Genome Sequencing as a Clinical
Diagnostic Test 64
6 Patterns of Inheritance 66
Family Studies 66
Mendelian Inheritance 66
Multiple Alleles and Complex Traits 75
Anticipation 75
Mosaicism 76
Uniparental Disomy 77
Genomic Imprinting 77
Mitochondrial Inheritance 80
7 Population and Mathematical Genetics 83
Allele Frequencies in Populations 83
Genetic Polymorphism 88
Segregation Analysis 88
Genetic Linkage 89
Medical and Societal Intervention 92
Conclusion 93
8 Risk Calculation 94
24 Probability Theory 94
Autosomal Dominant Inheritance 95
Autosomal Recessive Inheritance 97
Sex-Linked Recessive Inheritance 98
The Use of Linked Markers 99
Bayes’ Theorem and Prenatal Screening 99
Empiric Risks 100
9 Developmental Genetics 102
Fertilization and Gastrulation 102
Developmental Gene Families 103
The Pharyngeal Arches 114
The Role of Cilia in Developmental
Abnormalities 115
v
vi Contents

The Limb as a Developmental Model 115 14 The Genetics of Cancer…and Cancer

Developmental Genes and Cancer 119 Genetics 177
Positional Effects and Developmental Genes 121 Differentiation Between Genetic and Environmental
Hydatidiform Moles 121 Factors in Cancer 177
Epigenetics and Development 121 Oncogenes 179
Sex Determination and Disorders of Tumor Suppressor Genes 182
Sex Development 123 Epigenetics and Cancer 185
Twinning 127 Genetics of Common Cancers 186
DNA Tumor Profiling and Mutation Signatures 188
SECTION B Genetic Counseling in Familial Cancer 193
GENETICS IN MEDICINE 15 Pharmacogenetics, Personalized Medicine
AND GENOMIC MEDICINE and the Treatment of Genetic Disease 200
Pharmacogenetics 200
10 Common Disease, Polygenic and Drug Metabolism 200
Multifactorial Genetics 130 Genetic Variations Revealed by the Effects of
Types and Mechanisms of Genetic Susceptibility 130 Drugs 201
Approaches to Demonstrating Genetic Susceptibility Personalized Medicine 202
to Common Diseases 131 Treatment of Genetic Disease 204
Polygenic Inheritance and the Normal Therapeutic Applications of Recombinant DNA
Distribution 132 Technology 206
Multifactorial Inheritance—the Liability/Threshold Gene Therapy 207
Model 133
RNA Modification 210
Identifying Genes That Cause Multifactorial
Targeted Gene Correction 210
Disorders 134
Stem Cell Therapy 210
Disease Models for Multifactorial Inheritance 137

11 Screening for Genetic Disease 144

Screening Those at High Risk 144
Carrier Testing for Autosomal Recessive and
X-Linked Disorders 144
Presymptomatic Diagnosis of Autosomal Dominant
Disorders 145
Ethical Considerations in Carrier Detection and
Predictive Testing 147
Population Screening 147
Criteria for a Screening Program 148
Prenatal and Postnatal Screening 149
Population Carrier Screening 151
Genetic Registers 152
12 Hemoglobin and the
Hemoglobinopathies 154
Structure of Hb 154
Developmental Expression of Hemoglobin 154
Globin Chain Structure 155
Synthesis and Control of Hemoglobin
Expression 156
Disorders of Hemoglobin 156
Clinical Variation of the Hemoglobinopathies 161
Antenatal and Newborn Hemoglobinopathy
Screening 162
SECTION C
CLINICAL GENETICS, COUNSELING,
AND ETHICS
16 Congenital Abnormalities, Dysmorphic
Syndromes, and Learning Disability 215
Incidence 215
Definition and Classification of Birth Defects 216
Genetic Causes of Malformations 219
Environmental Agents (Teratogens) 225
Malformations of Unknown Cause 228
Counseling 229
Learning Disability 229
17 Chromosome Disorders 236
Incidence of Chromosome Abnormalities 236
Disorders of the Sex Chromosomes 239
‘Classic’ Chromosome Deletion Syndromes 243
Microarray-CGH 245
Chromosome Disorders and Behavioral
Phenotypes 250
Chromosomal Breakage Syndromes 250
Indications for Chromosomal/Microarray-CGH
Analysis 253

13 Immunogenetics 164 18 Inborn Errors of Metabolism 255

Immunity 164 Disorders of Amino Acid and Peptide
Innate Immunity 164 Metabolism 255
Specific Acquired Immunity 166 Disorders of Carbohydrate Metabolism 260
Inherited Immunodeficiency Disorders 171 Disorders of Steroid Metabolism 261
Blood Groups 174 Disorders of Lipid and Lipoprotein Metabolism 262
 Contents vii

Lysosomal Storage Disorders 263
Disorders in the Metabolism of Purines, Pyrimidines,
and Nucleotides 265
Disorders of Porphyrin and Heme Metabolism 266
Disorders in the Metabolism of Trace Elements
and Metals 266
Peroxisomal Disorders 268
Disorders of Fatty Acid and Ketone Body
Metabolism 269
Disorders of Energy Metabolism 269
Prenatal Diagnosis of Inborn Errors of
Metabolism 271
19 Mainstream Monogenic Disorders
Neurological Disorders 273
The Hereditary Ataxias 274
Inherited Peripheral Neuropathies 275
Motor Neurone Disease (MND) 278
Neurocutaneous Disorders 278
Muscular Dystrophies 281
Respiratory Disorders 286
Inherited Cardiac Conditions (ICCs) 289
Connective Tissue Disorders 291
Renal Disorders 296
Blood Disorders 298
Assisted Conception and Implications for Genetic
Disease 313
Non-Invasive Prenatal Testing (NIPT) 314
Prenatal Treatment 315
21 Genetic Counseling 317
Definition 317
Establishing the Diagnosis 317
Calculating and Presenting the Risk 318
Discussing the Options 319
Communication and Support 319
Genetic Counseling—Directive or
273 Non-Directive? 319
Outcomes in Genetic Counseling 319
Special Issues in Genetic
Counseling 320
22 Ethical and Legal Issues in
Medical Genetics 323
General Principles 323
Ethical Dilemmas in the Genetics Clinic 325
Ethical Dilemmas and the Public Interest 327
Conclusion 330
Glossary 332

20 Prenatal Testing and Appendix: Websites and Clinical Databases 349

Reproductive Genetics 303 Multiple-Choice Questions 351
Techniques Used in Prenatal Diagnosis 303
Case-Based Questions 360
Prenatal Screening 306
Indications for Prenatal Testing 309 Multiple-Choice Answers 365
Special Problems in Prenatal Diagnosis 311
Case-Based Answers 375
Termination of Pregnancy 312
Preimplantation Genetic Diagnosis 313 Index 382
 Preface

“Reading maketh a full man; conference a ready man; and To these developments can be added the rapidly developing
writing an exact man.” applications of non-invasive prenatal testing and screening, as
Francis Bacon (1561–1626) well as nuclear cell transfer with mitochondrial donation to
treat some families devastated by mitochondrial disease.
It is more than five years since we last updated Emery’s Ele-
Advances in the use of genetic technologies for assisted repro-
ments and the task of producing a new edition has seemed
duction always provoke debate and controversy with
bigger and more daunting than ever. For the last edition we
entrenched, polarized views frequently pitted against each
mentioned the incoming technology of next generation sequenc-
other in the media. As we write this, the most recent advance
ing and the impact it was beginning to have on solving long-
to feature in this way is the use of gene editing, or CRISPR,
standing diagnostic conundrums, especially in a research
technology in the treatment of genetic disease. Together with
environment. Already, just a few years later, we owe so much
other novel approaches, there is more expectation than ever
to the scientists and bioinformaticians who make the technol-
before that families affected by genetic disease will in due
ogy work for patients and families affected by genetic disease.
course benefit from treatment strategies judiciously applied.
Gene discovery for rare disease has risen exponentially as a
We have made some major changes to this edition in our
result, and we now routinely request ‘panel’ tests for different
efforts to bring it up to date. We have re-ordered the chapters
phenotypes—whether for conditions of the RAS-MAPK
to a format that we believe is more logical and appropriate,
pathway or inherited eye disease—anything from 20 to 200
referred repeatedly to the use of new technologies, and added
genes. So, next generation sequencing is now very much a
much new clinical material to broaden its appeal as a basic text.
clinical and service tool as well, yielding a higher rate of diag-
As before, we hope this will prove useful to undergraduates
noses, and often at a price that is not much more than the cost
and postgraduates alike, and help them swim rather than sink
of testing one gene in the past.
when tackling the mysteries of medical genetics.
Whole exome or whole genome sequencing has given birth
to a huge field of ethical debate within and beyond the profes-
Peter Turnpenny and Sian Ellard
sions concerning ‘what to do’ with secondary or incidental
Exeter, United Kingdom
findings that have health implications. Europe and North
America are not always aligned in their views and practice in
these difficult areas, so the issues will continue to be discussed
and contested at length.

viii

As always, we feel privileged to be working in an area of
healthcare science and service that continues to be exciting and
captivating as the technologies and knowledge move forward
so inexorably. We work within teams and networks of very
talented colleagues who are similarly inspired and, even though
unaware, they contribute to this volume through their knowl-
edge, professional companionship and encouragement. For this
edition we particularly thank Dr Anna Murray (University of
Acknowledgments
Exeter Medical School) who helped with the merger of chap-
ters into the new ‘Common disease, Polygenic and Multifacto-
rial Genetics’. This edition includes a large number of new
clinical images, for which we must once again thank our patients
who have been so willing to share themselves in this way. We
are grateful to Elsevier, especially Alexandra Mortimer, for her
guidance and patience, particularly as several deadlines came
and went!
ix
 Dedication
To Alan Emery, a friend, mentor, and constant source of inspira-
tion and encouragement.
Alan E. H. Emery (c. 1983), Emeritus Professor of Human Genet-
ics & Honorary Fellow, University of Edinburgh, who first
established the Elements of Medical Genetics in 1968.
x
“The book was first conceived and published by the Univer-
sity of California Press in 1968 as Heredity, Disease, and Man:
Genetics in Medicine. However, when appointed Professor of
Human Genetics at Edinburgh in 1968 I decided I should
prefer the book to be published by Churchill Livingstone under
the title Elements of Medical Genetics, and made more acces-
sible to UK students with a cheaper paperback edition. This
was all achieved and has retained this format ever since. The
current 15th edition illustrates very clearly how the subject has
advanced so much over the intervening years.”
Alan Emery

Presenting historical truth is at least as challenging as the
pursuit of scientific truth and our view of human endeavors
down the ages is heavily biased in favor of winners—those who
have conquered on military, political, or, indeed, scientific
battlefields. The history of genetics in relation to medicine is
one of breathtaking discovery from which patients and families
have benefited hugely, but success will be measured by ongoing
progress in translating discoveries into both treatment and
prevention of disease, and we are privileged to be witnessing
such developments at the beginning of what promises to be a
dramatic and exciting era. But it is always inspiring to look back
with awe at what our forebears achieved with scarce resources
and sheer determination, sometimes aided by serendipity, in
order to lay the foundations of this dynamic science. A holistic
approach to science can be compared with driving a car:
without your eyes on the road ahead, you will crash and make
no progress; however, it is also essential to check the rear and
side mirrors regularly.
Gregor Mendel and the Laws
of Inheritance
Early Beginnings
Developments in genetics during the 20th century have been
truly spectacular. In 1900 Mendel’s principles were awaiting
rediscovery, chromosomes were barely visible, and the science
of molecular genetics did not exist. As we write this in 2016,
the published sequence of the entire human genome (2004)
already feels like a piece of history, chromosomes can be rapidly
analyzed to an extraordinary level of sophistication by micro­
array techniques, and next generation sequencing is transform­
ing gene discovery and genetic testing in a clinical setting. The
number of phenotypes with a known molecular basis is almost
5500 and the number of genes with a phenotype causing muta­
tion is almost 3400.
Genetics is relevant and important to almost every
medical discipline. Recent discoveries impinge not just on rare
genetic diseases and syndromes but also on many of the
common disorders of adult life that may be predisposed by
genetic variation, such as cardiovascular disease, psychiatric
illness, and cancer, not to mention influences on obesity, ath­
letic performance, musical ability, longevity, and a host of
physiological variations and tolerances. Clearly, a fundamental
grounding in genetics should be part of any undergraduate
medical curriculum.
We start with an overview of some of the most notable
milestones in the history of genetics and medical genetics,
followed by reviewing the overall impact of genetic factors in
causing disease. Finally, we mention some new developments
of major importance.
It is not known precisely when Homo sapiens first appeared
on this planet, but current estimates, based on the finding of
Chapter 1
The History and
Impact of Genetics
in Medicine
It’s just a little trick, but there is a long
story connected with it which it would take
too long to tell.
GREGOR MENDEL, IN CONVERSATION
WITH C.W. EICHLING
It has not escaped our notice that the
specific pairing we have postulated immediately
suggests a possible copying mechanism for the
genetic material.
WATSON & CRICK (APRIL 1953)
fossilized human bones in Ethiopia, suggest man was roaming
East Africa approximately 200,000 years ago. It is reasonable
to suppose that our early ancestors were as curious as ourselves
about matters of inheritance and, just as today, they would have
experienced the birth of babies with all manner of physical
defects. Engravings in Chaldea in Babylonia (modern-day Iraq)
dating back at least 6000 years show pedigrees documenting
the transmission of certain characteristics of the horse’s mane.
However, any early attempts to unravel the mysteries of genet­
ics would have been severely hampered by a total lack of
knowledge and understanding of basic processes such as con­
ception and reproduction.
Early Greek philosophers and physicians such as Aristotle
and Hippocrates concluded, not without a little prejudice, that
important human characteristics were determined by semen,
using menstrual blood as a culture medium and the uterus as
an incubator. Semen was thought to be produced by the whole
body; hence bald-headed fathers would beget bald-headed
sons. These ideas prevailed until the 17th century, when Dutch
scientists such as Leeuwenhoek and de Graaf recognized the
existence of sperm and ova, thus explaining how the female
could also transmit characteristics to her offspring.
The blossoming scientific revolution of the 18th and 19th
centuries saw a revival of interest in heredity by scientists and
physicians, among whom two names stand out. Pierre de
Maupertuis, a French naturalist, studied hereditary traits such
as extra digits (polydactyly) and lack of pigmentation (albi­
nism), and showed from pedigree studies that these two condi­
tions were inherited in different ways. Joseph Adams
(1756–1818), a British doctor, also recognized that different
mechanisms of inheritance existed and published A Treatise on
the Supposed Hereditary Properties of Diseases, which was
intended as a basis for genetic counseling. Also worthy of
mention is the English physician Edward Meryon (1809–1880),
who in 1851 was the first to provide a systematic clinico-
pathological study of three boys with the muscular disorder
1
2 The History and Impact of Genetics in Medicine

First filial cross

Pure bred Pure bred
Tall Short
TT t t

F1 Tt Tt Tt Tt
Tall

Second filial cross

Hybrid Hybrid
Tall Tall
Tt Tt

F2 TT Tt tT tt
Tall Short
FIGURE 1.2 An illustration of one of Mendel’s breeding experi-
ments and how he correctly interpreted the results.
FIGURE 1.1 Gregor Mendel. (Reproduced with permission from
BMJ Books.)

later eponymously attributed to the Frenchman, Guillaume
Duchenne (1806–1875), who described a larger series in 1868.
The modern scientific era really begins with the work of the
Austrian monk Gregor Mendel (1822–1884; Figure 1.1) who,
in 1865, presented the results of his breeding experiments on
garden peas to the Natural History Society of Brünn in Bohemia
(now Brno in the Czech Republic). Shortly after, Mendel’s
observations were published by that association in the Transac­
tions of the Society, where they remained largely unnoticed
until 1900, some 16 years after his death, when their impor­
tance was first recognized. In essence, Mendel’s work can be
considered as the discovery of genes and how they are inher­
ited. The term gene was first coined in 1909 by a Danish bota­
nist, Johannsen, and was derived from the term ‘pangen’,
introduced by De Vries. This term was itself a derivative of
the word ‘pangenesis,’ coined by Darwin in 1868. In recogni­
tion of Mendel’s foundational work, the term mendelian is now
part of scientific vocabulary, applied both to the different pat­
terns of inheritance and to disorders found to be the result of
defects in a single gene.
In his breeding experiments, Mendel studied contrasting
characters in the garden pea, using for each experiment variet­
ies that differed in only one characteristic. For example, he
noted that when strains bred for a feature such as tallness were
crossed with plants bred to be short all of the offspring in the
first filial or F1 generation were tall. If plants in this F1 genera­
tion were interbred, this led to both tall and short plants in a
ratio of 3 : 1 (Figure 1.2). Characteristics that were manifest
Mendel’s proposal was that the plant characteristics being
studied were each controlled by a pair of factors, one of which
was inherited from each parent. The pure-bred plants, with
two identical genes, used in the initial cross would now be
referred to as homozygous. The hybrid F1 plants, each of
which has one gene for tallness and one for shortness, would
be referred to as heterozygous. The genes responsible for these
contrasting characteristics are referred to as allelomorphs, or
alleles for short.
An alternative method for determining genotypes in off­
spring involves the construction of what is known as a Punnett
square (Figure 1.3). This is used further in Chapter 7 when
considering how genes segregate in large populations.
On the basis of Mendel’s plant experiments, three main
principles were established. These are known as the laws of
uniformity, segregation, and independent assortment.
Hybrid Tall
Gametes
T t
T TT Tt
Hybrid Tall

Gametes

in the F1 hybrids were referred to as dominant, whereas those

that reappeared in the F2 generation were described as being
recessive. On reanalysis it has been suggested that Mendel’s
results were ‘too good to be true’ in that the segregation ratios
he derived were suspiciously closer to the value of 3 : 1 than
the laws of statistics would predict. One possible explanation
is that he may have published only those results that best
agreed with his preconceived single-gene hypothesis. Whatever
the case, events have shown that Mendel’s interpretation of his
results was entirely correct.
t tT tt
FIGURE 1.3 A Punnett square showing the different ways in
which genes can segregate and combine in the second filial
cross from Figure 1.2. Construction of a Punnett square provides
a simple method for showing the possible gamete combinations
in different matings.

The Law of Uniformity
The law of uniformity refers to the fact that when two homo­
zygotes with different alleles are crossed, all of the offspring in
the F1 generation are identical and heterozygous. In other
words, the characteristics do not blend, as had been believed
previously, and can reappear in later generations.
The Law of Segregation
The law of segregation refers to the observation that each
person possesses two genes for a particular characteristic, only
one of which can be transmitted at any one time. Rare excep­
tions to this rule can occur when two allelic genes fail to separate
because of chromosome nondisjunction at the first meiotic
division (p. 30).
The Law of Independent Assortment
The law of independent assortment refers to the fact that
members of different gene pairs segregate to offspring inde­
pendently of one another. In reality, this is not always true, as
genes that are close together on the same chromosome tend to
be inherited together, because they are ‘linked’ (p. 89). There
are a number of other ways by which the laws of mendelian
inheritance are breached but, overall, they remain foundational
to our understanding of the science.
The Chromosomal Basis of Inheritance
As interest in mendelian inheritance grew, there was much
speculation as to how it actually occurred. At that time it was
also known that each cell contains a nucleus within which there
are several threadlike structures known as chromosomes, so
called because of their affinity for certain stains (chroma =
color, soma = body). These chromosomes had been observed
since the second half of the 19th century after development
of cytologic staining techniques. Human mitotic figures were
observed from the late 1880s, and it was in 1902 that Walter
Sutton, an American medical student, and Theodour Boveri, a
German biologist, independently proposed that chromosomes
could be the bearers of heredity (Figure 1.4). Subsequently,
A B
FIGURE 1.4 Chromosomes dividing into two daughter cells at different stages of cell division. A, Metaphase; B, anaphase;
C, telophase. The behavior of chromosomes in cell division (mitosis) is described at length in Chapter 3. (Photographs courtesy
Dr. K. Ocraft, City Hospital, Nottingham.)
The History and Impact of Genetics in Medicine 3
Thomas Morgan transformed Sutton’s chromosome theory
into the theory of the gene, and Alfons Janssens observed
the formation of chiasmata between homologous chromosomes
at meiosis. During the late 1920s and 1930s, Cyril Darlington
helped to clarify chromosome mechanics by the use of tulips
collected on expeditions to Persia. It was during the 1920s
that the term genome entered the scientific vocabulary, being
the fusion of genom (German for ‘gene’) and ome from
‘chromosome’.
When the connection between mendelian inheritance and
chromosomes was first made, it was thought that the normal
chromosome number in humans might be 48, although various
papers had come up with a range of figures. Key to the number
48 was a paper in 1921 from Theophilus Painter, an American
cytologist who had been a student of Boveri. In fact, Painter
had some preparations clearly showing 46 chromosomes, even
though he finally settled on 48. These discrepancies were prob­
ably from the poor quality of the material at that time; even
into the early 1950s, cytologists were counting 48 chromo­
somes. It was not until 1956 that the correct number of 46
was established by Tjio and Levan, 3 years after the correct
structure of DNA had been proposed. Within a few years, it
was shown that some disorders in humans could be caused by
loss or gain of a whole chromosome as well as by an abnormality
in a single gene. Chromosome disorders are discussed at length
in Chapter 17. Some chromosome aberrations, such as trans­
locations, can run in families (p. 35), and are sometimes said
to be segregating in a mendelian fashion.
DNA as the Basis of Inheritance
Whilst James Watson and Francis Crick are justifiably credited
with discovering the structure of DNA in 1953, they were
attracted to working on it only because of its key role as the
genetic material, as established in the 1940s. Formerly many
believed that hereditary characteristics were transmitted by
proteins, until it was appreciated that their molecular structure
was far too cumbersome. Nucleic acids were actually discov­
ered in 1849. In 1928 Fred Griffith, working on two strains of
C
4 The History and Impact of Genetics in Medicine
Streptococcus, realized that characteristics of one strain could
be conferred on the other by something that he called the
transforming principle. In 1944, at the Rockefeller Institute in
New York, Oswald Avery, Maclyn McCarty, and Colin MacLeod
identified DNA as the genetic material while working on
Streptococcus pneumoniae. Even then, many in the scientific
community were sceptical; DNA was only a simple molecule
with lots of repetition of four nucleic acids—very boring! The
genius of Watson and Crick, at Cambridge, was to hit on a
structure for DNA, the elegant double helix, that would
explain the very essence of biological reproduction. Crucial to
their discovery were the x-ray crystallography images captured
by the often-overlooked graduate technician Raymond Gosling,
working under the supervision of Maurice Wilkins and Rosalind
Franklin in John Randall’s laboratory at King’s College, London.
This was merely the beginning, for it was necessary to dis­
cover the process whereby DNA, in discrete units called genes,
issues instructions for the precise assembly of proteins, the
building blocks of tissues. The sequence of bases in DNA, and
the sequence of amino acids in protein, the genetic code, was
unravelled in some elegant biochemical experiments in the
1960s and it became possible to predict the base change in
DNA that led to the amino-acid change in the protein. Further
experiments, involving Francis Crick, Paul Zamecnik, and
Mahlon Hoagland, identified the molecule transfer RNA
(tRNA) (p. 15), which directs genetic instructions via amino
acids to intracellular ribosomes, where protein chains are
produced. Confirmation of these discoveries came with DNA
sequencing methods and the advent of recombinant DNA
techniques. Interestingly, however, the first genetic trait to be
characterized at the molecular level had already been identified
in 1957 by laborious sequencing of the purified proteins. This
was sickle-cell anemia, in which the mutation affects the
amino-acid sequence of the blood protein hemoglobin.
The Fruit Fly
Before returning to historical developments in human genetics,
it is worth a brief diversion to consider the merits of an unlikely
creature that has proved to be of great value in genetic research.
The fruit fly, Drosophila, possesses several distinct advantages
for the study of genetics:
1. It can be bred easily in a laboratory.
2. It reproduces rapidly and prolifically at a rate of 20 to 25
generations per annum.
3. It has a number of easily recognized characteristics, such as
curly wings and a yellow body, which follow mendelian
inheritance.
4. Drosophila melanogaster, the species studied most fre­
quently, has only four pairs of chromosomes, each of which
has a distinct appearance so that they can be identified
easily.
5. The chromosomes in the salivary glands of Drosophila
larvae are among the largest known in nature, being at least
100 times bigger than those in other body cells.
In view of these unique properties, fruit flies were used exten­
sively in early breeding experiments, contributing enormously
to developmental biology, where knowledge of gene homology
throughout the animal kingdom has enabled scientists to
identify families of genes that are important in human embryo­
genesis (see Chapter 9). The sequencing of the 180 million
base pairs of the Drosophila melanogaster genome was com­
pleted in late 1999.
The Origins of Medical Genetics
In addition to the previously mentioned Pierre de Maupertuis
and Joseph Adams, whose curiosity was aroused by polydactyly
and albinism, there were other pioneers. John Dalton, of
atomic theory fame, observed that some conditions, notably
color blindness and hemophilia, show what is now referred to
as sex- or X-linked inheritance; color blindness is still occasion­
ally referred to as daltonism.
In 1900 Mendel’s work resurfaced. His papers were quoted
almost simultaneously by three European botanists—De
Vries (Holland), Correns (Germany), and Von Tschermak
(Austria)—and this marked the real beginning of medical
genetics, providing an enormous impetus for the study of
inherited disease. Credit for the first recognition of a single-
gene trait is shared by William Bateson and Archibald Garrod,
who together proposed that alkaptonuria was a rare recessive
disorder. In this relatively benign condition, urine turns dark
on standing or on exposure to alkali because of the patient’s
inability to metabolize homogentisic acid (p. 258). Young
children show skin discoloration in the napkin (diaper) area and
affected adults may develop arthritis in large joints. Realizing
that this was an inherited disorder involving a chemical process,
Garrod coined the term inborn error of metabolism in 1908,
though his work was largely ignored until the mid-20th century
when electrophoresis and chromatography revolutionized bio­
chemistry. Several hundred such disorders have now been
identified, giving rise to the field of biochemical genetics (see
Chapter 18).
During the course of the 20th century, it gradually became
clear that hereditary factors were implicated in many condi­
tions and that different genetic mechanisms were involved.
Traditionally, hereditary conditions have been considered under
the headings of single gene, chromosomal, and multifactorial.
Increasingly, it is becoming clear that the interplay of different
genes (polygenic inheritance) is important in disease, and that
a further category—acquired somatic genetic disease—should
also be included.
Single-Gene Disorders
In addition to alkaptonuria, Garrod suggested that albinism and
cystinuria could also be recessive. Soon other examples fol­
lowed, leading to an explosion in knowledge and disease
delineation. By 1966 almost 1500 single-gene disorders or traits
had been identified, prompting the publication by an American
physician, Victor McKusick (Figure 1.5), of a catalog of all
known single-gene conditions. By 1998, when the 12th edition
of the catalog was published, it contained more than 8500
entries. The growth of ‘McKusick’s Catalog’ was exponential
and became the electronic Online Mendelian Inheritance in
Man (OMIM) (see Appendix) in 1987. By August 2016,
OMIM contained more than 23,600 entries.
Chromosome Abnormalities
Improved techniques for studying chromosomes led to the
demonstration in 1959 that the presence of an additional
number 21 chromosome (trisomy 21) results in Down syn­
drome. Other similar discoveries followed rapidly—Klinefelter
and Turner syndromes—also in 1959. The identification of
chromosome abnormalities was further aided by the develop­
ment of banding techniques in 1970 (p. 26). These enabled
reliable identification of individual chromosomes and helped
confirm that loss or gain of even a very small segment of a

FIGURE 1.5 Victor McKusick in 1994, whose studies and cata-
logs have been so important to medical genetics.
chromosome can have devastating effects on human develop­
ment (see Chapter 17).
Later it was shown that several rare conditions featuring
learning difficulties and abnormal physical features are due to
loss of such a tiny amount of chromosome material that no
abnormality can be detected using even the most high-powered
light microscope. These conditions are referred to as microde­
letion syndromes (p. 245) and can be diagnosed using a tech­
nique known as FISH (fluorescent in situ hybridization),
which combines conventional chromosome analysis (cytoge-
netics) with newer DNA diagnostic technology (molecular
genetics) (see Chapter 5). Today, the technique of microarray
CGH (comparative genomic hybridization) has revolutionized
clinical investigation through the detection of subtle genomic
imbalances (p. 54) and, where it is available, become the first-
line test of choice.
Multifactorial Disorders
Francis Galton, a cousin of Charles Darwin, had a long-standing
interest in human characteristics such as stature, physique, and
intelligence. Much of his research was based on the study of
identical twins, in whom it was realized that differences in
these parameters must be largely the result of environmental
influences. Galton introduced to genetics the concept of the
regression coefficient as a means of estimating the degree of
resemblance between various relatives. This concept was later
extended to incorporate Mendel’s discovery of genes, to try to
explain how parameters such as height and skin color could be
determined by the interaction of many genes, each exerting a
small additive effect. This is in contrast to single-gene charac­
teristics in which the action of one gene is exerted indepen­
dently, in a nonadditive fashion.
This model of quantitative inheritance is now widely
accepted and has been adapted to explain the pattern of
inheritance observed for many relatively common conditions
(see Chapter 10). These include congenital malformations
such as cleft lip and palate, and late-onset conditions such as
hypertension, diabetes mellitus, and Alzheimer disease. The
The History and Impact of Genetics in Medicine 5
prevailing view is that genes at several loci interact to generate
a susceptibility to the effects of adverse environmental trigger
factors. Recent research has confirmed that many genes are
involved in most of these adult-onset disorders, although
progress in identifying specific susceptibility loci has been
disappointingly slow. It has also emerged that in some condi­
tions, such as type I diabetes mellitus, different genes can exert
major or minor effects in determining susceptibility (p. 130).
Overall, multifactorial or polygenic conditions are now known
to make a major contribution to chronic illness in adult life (see
Chapter 10).
Acquired Somatic Genetic Disease
Not all genetic errors are present from conception. Many bil­
lions of cell divisions (mitoses) occur in the course of an average
human lifetime. During each mitosis, there is an opportunity
for both single-gene mutations to occur, because of DNA copy
errors, and for numerical chromosome abnormalities to arise as
a result of errors in chromosome separation. Accumulating
somatic mutations and chromosome abnormalities are now
known to play a major role in causing cancer (see Chapter 14),
and they probably also explain the rising incidence with age of
many other serious illnesses, as well as the aging process itself.
It is therefore necessary to appreciate that not all disease with
a genetic basis is hereditary.
Before considering the impact of hereditary disease, it is
helpful to introduce a few definitions.
Incidence
Incidence refers to the rate at which new cases occur. Thus, if
the birth incidence of a particular condition equals 1 in 1000,
then on average 1 in every 1000 newborn infants is affected.
Prevalence
This refers to the proportion of a population affected at any
one time. The prevalence of a genetic disease is usually less
than its birth incidence, either because life expectancy is
reduced or because the condition shows a delayed age of onset.
Frequency
Frequency is a general term that lacks scientific specificity,
although the word is often taken as being synonymous with
incidence when calculating gene ‘frequencies’ (see Chapter 7).
Congenital
Congenital means that a condition is present at birth. Thus,
cleft palate represents an example of a congenital malforma-
tion. Not all genetic disorders are congenital in terms of age of
onset (e.g., Huntington disease), nor are all congenital abnor­
malities genetic in origin (e.g., fetal disruptions, as discussed in
Chapter 16).
DNA Sequencing
The ability to search for mutations in human DNA to identify
the causes of genetic disease clearly depended on being able to
sequence DNA, which initially was very laborious. The first
really practical method was developed by Walter Gilbert, with
sequencing based on a cleavage at specific bases after chemical
modification of DNA. But it was Frederick Sanger’s (Figure
1.6) ingenious technique (1975), based on dideoxynucleotide
chain termination, that proved efficient, reliable and popular,
not least because of low radioactivity. These techniques formed
the basis for embarking on the Human Genome Project, though
6 The History and Impact of Genetics in Medicine
FIGURE 1.6 Frederick Sanger, who invented the most widely
used method of DNA sequencing, and won two Nobel Prizes.
the first genome to be sequenced was that of a bacteriophage
in 1977. Both men were awarded the Nobel Prize in 1980 for
this achievement, which was Sanger’s second—he was awarded
the Chemistry Prize in 1958 for determining the amino acid
sequence of insulin (he remains the only British scientist to
have won two Nobel Prizes). ‘Sanger sequencing’ remains vital
to human molecular genetics, and the term is as prominent in
the language of genetics as ‘mendelian inheritance’ and ‘McKu­
sick’s Catalog’.
The Impact of Genetic Disease
During the 20th century, improvements in all areas of medicine,
most notably public health and therapeutics, resulted in chang­
ing patterns of disease, with increasing recognition of the role
of genetic factors at all ages. For some parameters, such as
perinatal mortality, the actual numbers of cases with exclusively
genetic causes have probably remained constant but their rela-
tive contribution to overall figures has increased as other causes,
such as infection, have declined. For other conditions, such as
the chronic diseases of adult life, the overall contribution of
genetics has almost certainly increased as greater life expec­
tancy has provided more opportunity for adverse genetic and
environmental interaction to manifest itself, for example in
Alzheimer disease, macular degeneration, cardiomyopathy, and
diabetes mellitus. Today there is much debate about the rela­
tive contributions of genetic and environmental factors in the
increasing prevalence of obesity in the developed world.
Consider the impact of genetic factors in disease at different
ages from the following observations.
Spontaneous Miscarriages
A chromosome abnormality is present in 40% to 50% of all
recognized first-trimester pregnancy loss. Approximately 1 in
4 of all pregnancies results in spontaneous miscarriage, so at
least 10% of all recognized conceptions are chromosomally
abnormal (p. 236). This value would be much higher if unrec­
ognized pregnancies could also be included, and it is likely that
a significant proportion of miscarriages with normal chromo­
somes do in fact have catastrophic submicroscopic genetic
errors.
Newborn Infants
Up to 3% of neonates have at least one major congenital
abnormality, of which at least 50% are caused exclusively or
partially by genetic factors (see Chapter 16), with the inci­
dences of chromosome abnormalities and single-gene disorders
in neonates being roughly 1 in 200 and 1 in 100, respectively.
Childhood
By school age roughly 12-14% of children show problems of
developmental origin. Genetic disorders account for at least
50% of all childhood blindness, at least 50% of all childhood
deafness, and at least 50% of all cases of severe learning diffi­
culty. In developed countries, genetic disorders and congenital
malformations together also account for 30% of all childhood
hospital admissions and 40% to 50% of all childhood deaths.
Adult Life
Approximately 1% of all malignancies are primarily caused by
single-gene inheritance, and between 5% and 10% of common
cancers such as those of the breast, colon, and ovary have a
strong hereditary component. By the age of 25 years, 5% of the
population will have a disorder in which genetic factors play an
important role. Taking into account the genetic contribution to
cancer and cardiovascular diseases, such as coronary artery
occlusion and hypertension, it has been estimated that more
than 50% of the older adult population in developed countries
will have a genetically determined medical problem.
Major New Developments
The study of genetics and its role in causing human disease is
now widely acknowledged as being among the most exciting and
influential areas of medical research. Since 1962 when Francis
Crick, James Watson, and Maurice Wilkins gained acclaim for
their elucidation of the structure of DNA, the Nobel Prize for
Medicine and/or Physiology has been won on 24 occasions, and
the Chemistry Prize on six occasions, by scientists working in
human and molecular genetics or related fields (Table 1.1).
These pioneering studies have spawned a thriving molecular
technology industry with applications as diverse as the develop­
ment of genetically modified disease-resistant crops, the use of
genetically engineered animals to produce therapeutic drugs,
and the possible introduction of DNA-based vaccines for condi­
tions such as malaria, not to mention the growing availability of
affordable direct-to-consumer testing for disease susceptibility.
Pharmaceutical companies are investing heavily in the DNA-
based pharmacogenomics—drug therapy tailored to personal
genetic makeup.
The Human Genome Project (HGP)
In 1988 a group of visionary scientists in the United
States persuaded Congress to fund a coordinated interna­
tional program to sequence the entire human genome. The
program would run from 1990 to 2005 and US$3 billion were
initially allocated to the project. Some 5% of the budget was
allocated to study the ethical and social implications of the new
 The History and Impact of Genetics in Medicine 7

Table 1.1 Genetic Discoveries That Have Led to the Award of the Nobel Prize for Medicine or Physiology and/
or Chemistry, 1962–2012
Year Prize Winners Discovery Year Prize Winners Discovery
1962 Francis Crick The molecular structure 1995 Edward Lewis Homeotic and other
James Watson of DNA Christiane Nüsslein-Volhard developmental genes
Maurice Wilkins Eric Wieschaus
1965 François Jacob Genetic regulation 1997 Stanley Prusiner Prions
Jacques Monod 1999 Günter Blobel Protein transport
André Lwoff signaling
1966 Peyton Rous Oncogenic viruses 2000 Arvid Carlsson Signal transduction in the
1968 Robert Holley Deciphering of the Paul Greengard nervous system
Gobind Khorana genetic code Eric Kandel
Marshall Nireberg 2001 Leland Hartwell Regulators of the cell
1972 Christian B. Anfisen Ribonuclease Timothy Hunt cycle
Stanford Moore Paul Nurse
William H. Stein 2002 Sydney Brenner Genetic regulation in
1975 David Baltimore Interaction between Robert Horritz development and
Renato Dulbecco tumor viruses and John Sulston programmed cell death
Howard Temin nuclear DNA (apoptosis)
1978 Werner Arber Restriction endonucleases 2006 Andrew Fire RNA interference
Daniel Nathans Craig Mello (Medicine)
Hamilton Smith Roger D. Kornberg Eukaryotic transcription
1980 Baruj Benacerraf Genetic control of (Chemistry)
Jean Dausset immunologic responses 2007 Mario Capecchi Gene modification by the
George Snell (Medicine) Martin Evans use of embryonic stem
Paul Berg Biochemistry of nucleic Oliver Smithies cells
Walter Gilbert acids (Chemistry) 2009 Elizabeth Blackburn The role of telomerase in
Frederick Sanger Carol Greider protecting
1983 Barbara McClintock Mobile genes Jack Szostak chromosome telomeres
(transposons) (Medicine)
1985 Michael Brown Cell receptors in familial Venkatraman Ramakrishnan Structure and function of
Joseph Goldstein hypercholesterolemia Thomas A. Steitz the ribosome
1987 Susumu Tonegawa Genetic aspects of Ada E. Yonath (Chemistry)
antibodies 2010 Robert G. Edwards In vitro fertilization
1989 Michael Bishop Study of oncogenes 2012 John B. Gurdon Mature cells
Harold Varmus (Medicine) Shinya Yamanaka reprogrammed to
Sidney Altman Catalytic properties of become pluripotent
Thomas R. Cech RNA (Chemistry) cells (Medicine)
1993 Richard Roberts ’Split genes’ (Medicine) Robert J. Lefkowitz G-protein coupled
Phillip Sharp Brian K. Kobilka receptors (Chemistry)
Kary B. Mullis DNA-based chemistry,
Michael Smith including the invention
of PCR (Chemistry)

knowledge in recognition of the enormous potential to influ­
ence public health policies, screening programs, and personal
choice. The project was likened to the Apollo moon mission in
terms of its complexity, although in practical terms the long-
term benefits are likely to be much more tangible. The draft
DNA sequence of 3 billion base pairs was completed success­
fully in 2000 and the complete sequence published ahead of
schedule in October 2004. Before the closing stages of the
project, it was thought that there might be approximately
100,000 coding genes that provide the blueprint for human life.
It has come as a surprise to many that the number is much
lower, and has been continually revised downwards with
current estimates at around 20,000. However, we have learned
that many genes have the capacity to perform multiple func­
tions, thus challenging traditional concepts of disease classifica­
tion. The HGP has now been succeeded by the Human
Variome Project, aimed at compiling and sharing the enormous
variation in human DNA sequence worldwide, all of which is
potentially possible since whole exome sequencing (WES) and
whole genome sequencing (WGS) are taking place on an
industrial scale in numerous population studies and, for the
direct benefit of patients, projects such as Deciphering Devel­
opmental Disorders (DDD) based at the Sanger Centre,
Cambridge, and 100 000 Genomes in the UK, and their equiva­
lent elsewhere. Indeed, WES in particular has facilitated a huge
surge in disease gene discovery since the last published edition
of this book. This has led to the exciting growth area of Bioin-
formatics, the science where biology, computer science, and
information technology merge into a single discipline that
encompasses gene maps, DNA sequences, comparative and
functional genomics, and a lot more. Familiarity with interlink­
ing databases is essential for the molecular geneticist, and
increasingly so for keen clinicians with an interest in genetics,
who will find OMIM a good place to start.
The Prospects for Treatment
Most genetic disease is resistant to conventional treatment so
that the prospect of successfully modifying the genetic code in
a patient’s cells is extremely attractive. Despite major invest­
ment and extensive research, success in humans has so far been
8 The History and Impact of Genetics in Medicine
limited to a few very rare immunologic disorders. For more
common conditions, such as cystic fibrosis, major problems
have been encountered, such as targeting the correct cell popu­
lations, overcoming the body’s natural defense barriers, and
identifying suitably nonimmunogenic vectors. However, the
availability of mouse models for genetic disorders, such as
cystic fibrosis (p. 286), Huntington disease (p. 273), and
Duchenne muscular dystrophy (p. 281), has greatly enhanced
research opportunities, particularly in unraveling the cell
biology of these conditions. In recent years there has been
increasing optimism for novel drug therapies and stem cell
treatment (p. 210), besides the prospects for gene therapy
itself (p. 207).
The Societal Impact of Advances
in Genetics
Each new advance in genetic technology has generated fresh
ethical concerns about how the science will be applied and
utilized in medicine, at the center of which is the recognition
that a person’s genetic make-up is fundamental to both their
identity and possible disease susceptibility. These issues are
explored in detail in Chapter 22. The most contentious field is
prenatal genetics and reproductive choice, though national legal
frameworks and cultural practices vary widely worldwide. The
controversy surrounding the early ability to perform prenatal
karyotyping for Down syndrome in the mid-1960s is mirrored
today in the technology that will make it possible to perform
detailed genetic screening of the unborn baby on cell-free fetal
DNA in the maternal circulation, or on embryos created
through in vitro fertilization. Great debate has taken place, and
will continue, concerning the disclosure of unexpected but
significant ‘incidental findings’ from WES or WGS carried out
for specific clinical purposes, and the possibility of all newborns
having their genome sequenced and screened is both techni­
cally feasible and has been seriously mooted at governmental
level. Many of the questions raised do not have easy or straight­
forward answers, which means that there will be a great need
for appropriately trained clinicians and counselors to meet the
public demands for the foreseeable future.
FURTHER READING
Baird, P.A., Anderson, T.W., Newcombe, H.B., Lowry, R.B., 1988.
Genetic disorders in children and young adults: a population study.
Am. J. Hum. Genet. 42, 677–693.
A comprehensive study of the incidence of genetic disease in a large
Western urban population.
The first report of the complete sequencing of a human
chromosome.
Emery, A.E.H., 1989. Portraits in medical genetics—Joseph Adams
1756–1818. J. Med. Genet. 26, 116–118.
An account of the life of a London doctor who made remarkable
observations about hereditary disease in his patients.
Emery, A.E.H., Emery, M.L.H., 2011. The history of a genetic disease:
Duchenne muscular dystrophy or Meryon’s disease, second ed.
Oxford University Press, Oxford, UK.
Describes the life and work of Edward Meryon, the first physician
to describe Duchenne muscular dystrophy in detail.
Garrod, A.E., 1902. The incidence of alkaptonuria: a study in chemical
individuality. Lancet ii, 1916–1920.
A landmark paper in which Garrod proposed that alkaptonuria
could show mendelian inheritance and also noted that ‘the mating of
first cousins gives exactly the conditions most likely to enable a rare,
and usually recessive, character to show itself ’.
Orel, V., 1995. Gregor Mendel: the first geneticist. Oxford University
Press, Oxford.
A detailed biography of the life and work of the Moravian monk
who was described by his abbot as being ‘very diligent in the study
of the sciences but much less fitted for work as a parish priest’.
Sanger, F., Coulson, A.R., 1975. A rapid method for determining
sequences in DNA by primed synthesis with DNA polymerase.
J. Mol. Biol. 94, 441–448.
Watson, J., 1968. The double helix. Atheneum, New York.
The story of the discovery of the structure of DNA, through the eyes
of Watson himself.
Databases
Online Mendelian Inheritance in Man:
http://www.ncbi.nlm.nih.gov/omim
For Literature:
http://www.ncbi.nlm.nih.gov/PubMed/
http://scholar.google.com/
Genome:
http://www.ncbi.nlm.nih.gov/omim/GenBank
http://www.hgmd.cf.ac.uk (human, Cardiff)
http://www.ensembl.org (human, comparative, European, Cambridge)
http://genome.ucsc.edu (American browser)
http://www.humanvariomeproject.org/
ELEMENTS
1 A characteristic manifest in a hybrid (heterozygote) is
dominant. A recessive characteristic is expressed only in an
individual with two copies of the mutated gene (i.e., a
homozygote).
2 Mendel proposed that each individual has two genes for
each characteristic: one is inherited from each parent and
one is transmitted to each child. Genes at different loci act
and segregate independently.
3 Chromosome separation at cell division facilitates gene
segregation.
4 Genetic disorders are present in at least 2% of all neonates,
accounting for at least 50% of childhood blindness,
deafness, learning difficulties and deaths.
5 From the rediscovery of Mendel’s genetic research on peas,
to the full sequencing of the human genome, almost
exactly 100 years elapsed.
6 Molecular genetics and cell biology are at the forefront of
medical research, combined with the discipline of
bioinformatics, and hold the promise of novel forms of
treatment for genetic diseases.
 SECTION A
The Scientific Basis
of Human Genetics

Chapter 2
The Cellular and
Molecular Basis of
Inheritance
The hereditary material is present in the nucleus of the cell, There is nothing, Sir, too little for so little a
whereas protein synthesis takes place in the cytoplasm. What creature as man.
is the chain of events that leads from the gene to the final
product?
It is by studying little things that we attain the
This chapter covers basic cellular biology outlining the great art of having as little misery and as much
structure of DNA, the process of DNA replication, the types happiness as possible.
of DNA sequences, gene structure, the genetic code, the SAMUEL JOHNSON
processes of transcription and translation, the various types of
mutations, mutagenic agents, and DNA repair.

The Cell complex arrangement of very fine, highly convoluted, intercon-

Within each cell of the body, visible with the light microscope, necting channels, the endoplasmic reticulum. The endoplasmic
is the cytoplasm and a darkly staining body, the nucleus, the reticulum, in association with the ribosomes, is involved in the
latter containing the hereditary material in the form of chro- biosynthesis of proteins and lipids. Also situated within the
mosomes (Figure 2.1). The phospholipid bilayer of the plasma cytoplasm are other even more minute cellular organelles that
membrane protects the interior of the cell but remains selec- can be visualized only with an electron microscope. These
tively permeable and has integral proteins involved in recogni- include the Golgi apparatus, which is responsible for the secre-
tion and signaling between cells. The nucleus has a darkly tion of cellular products, the mitochondria, which are involved
staining area, the nucleolus. The nucleus is surrounded by a in energy production through the oxidative phosphorylation
membrane, the nuclear envelope, which separates it from the metabolic pathways, and the peroxisomes (p. 268) and lyso-
cytoplasm but still allows communication through nuclear somes, both of which are involved in the degradation and
pores. disposal of cellular waste material and toxic molecules.
The cytoplasm contains the cytosol, which is semifluid in
consistency, containing both soluble elements and cytoskeletal DNA: The Hereditary Material
structural elements. In addition, in the cytoplasm there is a
Composition
Nucleic acid is composed of a long polymer of individual
Nuclear Mitochondrion
molecules called nucleotides. Each nucleotide is composed of
Golgi complex a nitrogenous base, a sugar molecule, and a phosphate molecule.
envelope
Cytoplasm The nitrogenous bases fall into two types, purines and pyrimi-
Smooth
endoplasmic dines. The purines include adenine and guanine; the pyrimidines
reticulum include cytosine, thymine, and uracil.
There are two different types of nucleic acid, ribonucleic
Chromatin
acid (RNA), which contains the five-carbon sugar ribose, and
Rough deoxyribonucleic acid (DNA), in which the hydroxyl group at
endoplasmic
reticulum
the 2 position of the ribose sugar is replaced by a hydrogen
(i.e., an oxygen molecule is lost, hence ‘deoxy’). DNA and
RNA both contain the purine bases adenine and guanine
Ribosomes
and the pyrimidine cytosine, but thymine occurs only in DNA
Nucleolus and uracil is found only in RNA.
RNA is present in the cytoplasm and in particularly high
Lysosome concentrations in the nucleolus of the nucleus. DNA, on the
other hand, is found mainly in the chromosomes.

Nucleus Structure
For genes to be composed of DNA, it is necessary that the latter
Centriole
should have a structure sufficiently versatile to account for the
FIGURE 2.1 Diagrammatic representation of an animal cell. great variety of different genes and yet, at the same time, be
9
10 The Cellular and Molecular Basis of Inheritance

able to reproduce itself in such a manner that an identical
replica is formed at each cell division. In 1953, Watson and
Crick, based on x-ray diffraction studies by themselves and
others, proposed a structure for the DNA molecule that fulfilled
all the essential requirements. They suggested that the DNA
molecule is composed of two chains of nucleotides arranged in
a double helix. The backbone of each chain is formed by phos-
phodiester bonds between the 3′ and 5′ carbons of adjacent
sugars, the two chains being held together by hydrogen bonds
between the nitrogenous bases, which point in toward the
center of the helix. Each DNA chain has a polarity determined
by the orientation of the sugar–phosphate backbone. The asym-
metric ends of the DNA chains are called the 5′ and 3′ ends,
with the 5′ end having a terminal phosphate group and the 3′
end a terminal hydroxyl group. In the DNA duplex, the 5′ end
of one strand is opposite the 3′ end of the other, that is, they
have opposite orientations and are said to be antiparallel.
The arrangement of the bases in the DNA molecule is not
random. A purine in one chain always pairs with a pyrimidine
in the other chain, with specific pairing of the base pairs:
guanine in one chain always pairs with cytosine in the other
chain, and adenine always pairs with thymine, so that this base
pairing forms complementary strands (Figure 2.2). For their
work Watson and Crick, along with Maurice Wilkins, were
awarded the Nobel Prize for Medicine or Physiology in 1962
(p. 7).
Replication
The process of DNA replication provides an answer to the
question of how genetic information is transmitted from one
generation to the next. During nuclear division the two strands
of the DNA double helix separate through the action of enzyme
DNA helicase, each DNA strand directing the synthesis of a
complementary DNA strand through specific base pairing,
resulting in two daughter DNA duplexes that are identical to
the original parent molecule. In this way, when cells divide, the
genetic information is conserved and transmitted unchanged to
each daughter cell. The process of DNA replication is termed
semiconservative, because only one strand of each resultant
daughter molecule is newly synthesized.
DNA replication, through the action of the enzyme DNA
polymerase, takes place at multiple points known as origins of
replication, forming bifurcated Y-shaped structures known as
replication forks. The synthesis of both complementary anti-
parallel DNA strands occurs in the 5′ to 3′ direction. One
strand, known as the leading strand, is synthesized as a con-
tinuous process. The other strand, known as the lagging strand,
is synthesized in pieces called Okazaki fragments, which are
then joined together as a continuous strand by the enzyme
DNA ligase (Figure 2.3A).
DNA replication progresses in both directions from these
points of origin, forming bubble-shaped structures, or replica-
tion bubbles (see Figure 2.3B). Neighboring replication origins
are approximately 50 to 300 kilobases (kb) apart and occur in
clusters or replication units of 20 to 80 origins of replication.
DNA replication in individual replication units takes place at
different times in the S phase of the cell cycle (p. 30), adjacent
replication units fusing until all the DNA is copied, forming
two complete identical daughter molecules.
Chromosome Structure
The idea that each chromosome is composed of a single DNA
double helix is an oversimplification. A chromosome is very

3'-Hydroxyl

5' 3'
5'-Phosphate Deoxyribose OH

P
O
CH2
O A T CH2
P

P
O
CH2
O G C CH2
P
Hydrogen
bonds
P
O
CH2
O T A CH2
P

P
O
CH2
O C G CH2
P

OH 5'-Phosphate
5' 3'
A 3'-Hydroxyl B
FIGURE 2.2 DNA double helix. A, Sugar-phosphate backbone and nucleotide pairing of the DNA double helix (P, phosphate; A,
adenine; T, thymine; G, guanine; C, cytosine). B, Representation of the DNA double helix.
 The Cellular and Molecular Basis of Inheritance 11

5'
3' Lagging
3' strand
5'
3'
5' Leading
5' strand
3'
5'
3'
'
3' 3' 5
5'
3'
5'
5'
3'
5’
3'
3' 5'
3' 3' 5'
5'
3'
5'
5'
New Old
3'
A B strands strands
FIGURE 2.3 DNA replication. A, Detailed diagram of DNA replication at the site of origin in the replication fork showing asymmetric
strand synthesis with the continuous synthesis of the leading strand and the discontinuous synthesis of the lagging strand with
ligation of the Okazaki fragments. B, Multiple points of origin and semiconservative mode of DNA replication.

much wider than the diameter of a DNA double helix. In
addition, the amount of DNA in the nucleus of each cell in
humans means that the total length of DNA contained in the
chromosomes, if fully extended, would be several meters long!
In fact, the total length of the human chromosome comple-
ment is less than half a millimeter.
The packaging of DNA into chromosomes involves several
orders of DNA coiling and folding. In addition to the primary
coiling of the DNA double helix, there is secondary coiling
around spherical histone ‘beads’, forming what are called
nucleosomes. There is a tertiary coiling of the nucleosomes to
form the chromatin fibers that form long loops on a scaffold
of nonhistone acidic proteins, which are further wound in a
tight coil to make up the chromosome as visualized under the
light microscope (Figure 2.4), the whole structure making up
the so-called solenoid model of chromosome structure.
Types of DNA Sequence
DNA, if denatured, will reassociate as a duplex at a rate that
is dependent on the proportion of unique and repeat sequences
present, the latter occurring more rapidly. Analysis of the
results of the kinetics of the reassociation of human DNA have
shown that approximately 60% to 70% of the human genome
consists of single- or low-copy number DNA sequences. The
remainder of the genome, 30% to 40%, consists of either

DNA double Nucleosomes Chromatin Extended section Loops of Metaphase

helix fiber of chromosome chromatin fiber chromosome
FIGURE 2.4 Simplified diagram of proposed solenoid model of DNA coiling that leads to the visible structure of the chromosome.
12 The Cellular and Molecular Basis of Inheritance

the genome occurring on different chromosomes, such as the

Box 2.1 Types of DNA Sequence
Nuclear (∼3 × 109 bp)
Genes (∼20,000)
Unique single copy
Multigene families
Classic gene families
Gene superfamilies
Extragenic DNA (unique/low copy number or moderate/
highly repetitive)
Tandem repeat
Satellite
Minisatellite
Telomeric
Hypervariable
Microsatellite
Interspersed
Short interspersed nuclear elements
Long interspersed nuclear elements
Mitochondrial (16.6 kb, 37 genes)
Two rRNA genes
22 tRNA genes
moderately or highly repetitive DNA sequences that are not
transcribed. This latter portion consists of mainly satellite
DNA and interspersed DNA sequences (Box 2.1).
Nuclear Genes
It is estimated that there are between 20,000 and 25,000 genes
in the nuclear genome. The distribution of these genes varies
greatly between chromosomal regions. For example, hetero-
chromatic and centromeric (p. 25) regions are mostly noncod-
ing, with the highest gene density observed in subtelomeric
regions. Chromosomes 19 and 22 are gene rich, whereas 4 and
18 are relatively gene poor. The size of genes also shows great
variability: from small genes with single exons to the TTN gene
which encodes the largest known protein in the human body
and has not only the largest number of exons (363) in any
known gene, but also the single largest exon (17,106 bp).
Unique Single-Copy Genes
Most human genes are unique single-copy genes coding for
polypeptides that are involved in or carry out a variety of cel-
lular functions. These include enzymes, hormones, receptors,
and structural and regulatory proteins.
Multigene Families
Many genes have similar functions, having arisen through gene
duplication events with subsequent evolutionary divergence
making up what are known as multigene families. Some are
found physically close together in clusters; for example, the
α- and β-globin gene clusters on chromosomes 16 and 11
(Figure 2.5), whereas others are widely dispersed throughout
HOX homeobox gene family (p. 107).
Multigene families can be split into two types, classic gene
families that show a high degree of sequence homology and
gene superfamilies that have limited sequence homology but
are functionally related, having similar structural domains.
Classic Gene Families
Examples of classic gene families include the numerous copies
of genes coding for the various ribosomal RNAs, which are
clustered as tandem arrays at the nucleolar organizing regions
on the short arms of the five acrocentric chromosomes (p. 25),
and the different transfer RNA (p. 16) gene families, which
are dispersed in numerous clusters throughout the human
genome.
Gene Superfamilies
Examples of gene superfamilies include the HLA (human
leukocyte antigen) genes on chromosome 6 (p. 170) and the
T-cell receptor genes, which have structural homology with the
immunoglobulin (Ig) genes (p. 170). It is thought that these
are almost certainly derived from duplication of a precursor
gene, with subsequent evolutionary divergence forming the Ig
superfamily.
Gene Structure
The original concept of a gene as a continuous sequence of
DNA coding for a protein was turned on its head in the early
1980s by detailed analysis of the structure of the human
β-globin gene. It was revealed that the gene was much longer
than necessary to code for the β-globin protein, containing
noncoding intervening sequences, or introns, that separate the
coding sequences or exons (Figure 2.6). Most human genes
contain introns, but the number and size of both introns and
exons is extremely variable. Individual introns can be far larger
than the coding sequences and some have been found to
contain coding sequences for other genes (i.e., genes occurring
within genes). Genes in humans do not usually overlap, being
separated from each other by an average of 30 kb, although
some of the genes in the HLA complex (p. 170) have been
shown to be overlapping.
Pseudogenes
Particularly fascinating is the occurrence of genes that closely
resemble known structural genes but which, in general, are not
functionally expressed: so-called pseudogenes. These are
thought to have arisen in two main ways: either by genes
undergoing duplication events that are rendered silent through
the acquisition of mutations in coding or regulatory elements,
or as the result of the insertion of complementary DNA
sequences, produced by the action of the enzyme reverse
transcriptase on a naturally occurring messenger RNA tran-
script, that lack the promoter sequences necessary for
expression.

5' ζ ψζ ψα1 α2 α1 θ 3' Extragenic DNA

Chromosome 16
The estimated 20,000 unique single-copy genes in humans
represent less than 2% of the genome encoding proteins. The
remainder of the human genome is made up of repetitive DNA
5' ψβ ε Gγ Aγ ψβ1 δ β 3'
Chromosome 11 sequences that are predominantly transcriptionally inactive. It
has been described as junk DNA, but some regions show
FIGURE 2.5 Representation of the α- and β-globin regions on evolutionary conservation and play a critical role in the regula-
chromosomes 16 and 11. tion of temporal and spatial gene expression.

Transcription
initiation
CAAT TATA
box box
Exon 1 Exon 2
5'
Promoter Intron 1
region
Translation
initiation
codon
(ATG)
FIGURE 2.6 Representation of a typical human structural gene.
Tandemly Repeated DNA Sequences
Tandemly repeated DNA sequences consist of blocks of tandem
repeats of noncoding DNA that can be either highly dispersed
or restricted in their location in the genome. Tandemly repeated
DNA sequences can be divided into three subgroups: satellite,
minisatellite, and microsatellite DNA.
Satellite DNA
Satellite DNA accounts for approximately 10% to 15% of the
repetitive DNA sequences of the human genome and consists
of very large series of simple or moderately complex, short,
tandemly repeated DNA sequences that are transcriptionally
inactive and are clustered around the centromeres of certain
chromosomes. This class of DNA sequences can be separated
on density-gradient centrifugation as a shoulder, or ‘satellite’,
to the main peak of genomic DNA, and has therefore been
referred to as satellite DNA.
Minisatellite DNA
Minisatellite DNA consists of two families of tandemly
repeated short DNA sequences: telomeric and hypervariable
minisatellite DNA sequences that are transcriptionally
inactive.
Telomeric DNA. The terminal portion of the telomeres of the
chromosomes (p. 25) contains 10 to 15 kb of tandem repeats
of a 6-base-pair (bp) DNA sequence known as telomeric DNA.
The telomeric repeat sequences are necessary for chromosomal
integrity in replication and are added to the chromosome by
an enzyme known as telomerase (p. 25).
Hypervariable minisatellite DNA. Hypervariable minisatellite
DNA is made up of highly polymorphic DNA sequences con-
sisting of short tandem repeats of a common core sequence.
The highly variable number of repeat units in different hyper-
variable minisatellites forms the basis of the DNA fingerprint-
ing technique developed by Professor Sir Alec Jeffreys in 1984
(p. 52).
Microsatellite DNA
Microsatellite DNA consists of tandem single, di-, tri-, and
tetra-nucleotide repeat base-pair sequences located throughout
the genome. Microsatellite repeats rarely occur within coding
sequences but trinucleotide repeats in or near genes are associ-
ated with certain inherited disorders (p. 54).
This variation in repeat number is thought to arise by incor-
rect pairing of the tandem repeats of the two complementary
DNA strands during DNA replication, or what is known as
The Cellular and Molecular Basis of Inheritance 13
Transcription
termination
Exon 3
3'
Intron 2
Translation Polyadenylation
termination signal
codon
(TAA)
slipped strand mispairing. Duplications or deletions of longer
sequences of tandemly repeated DNA are thought to arise
through unequal crossover of nonallelic DNA sequences on
chromatids of homologous chromosomes or sister chromatids
(p. 25).
Nowadays DNA microsatellites are used for forensic and
paternity tests (p. 52). They can also be helpful for gene
tracking in families with a genetic disorder but no identified
mutation (p. 52).
Highly Repeated Interspersed Repetitive
DNA Sequences
Approximately one-third of the human genome is made up of
two main classes of short and long repetitive DNA sequences
that are interspersed throughout the genome.
Short Interspersed Nuclear Elements
Approximately 5% of the human genome consists of some
750,000 copies of short interspersed nuclear elements, or
SINEs. The most common are DNA sequences of approxi-
mately 300 bp that have sequence similarity to a signal recogni-
tion particle involved in protein synthesis. They are called Alu
repeats because they contain an AluI restriction enzyme recog-
nition site.
Long Interspersed Nuclear Elements
Approximately 5% of the DNA of the human genome is made
up of long interspersed nuclear elements, or LINEs. The most
commonly occurring LINE, known as LINE-1 or an L1 element,
consists of more than 100,000 copies of a DNA sequence of
up to 6000 bp that encodes a reverse transcriptase.
The function of these interspersed repeat sequences is not
clear. Members of the Alu repeat family are flanked by short
direct repeat sequences and therefore resemble unstable DNA
sequences called transposable elements or transposons. Trans-
posons, originally identified in maize by Barbara McClintock
(p. 7), move spontaneously throughout the genome from one
chromosome location to another and appear to be ubiquitous
in the plant and animal kingdoms. It is postulated that Alu
repeats could promote unequal recombination, which could
lead to pathogenic mutations (p. 17) or provide selective
advantage in evolution by gene duplication. Both Alu and
LINE-1 repeat elements have been implicated as a cause of
mutation in inherited human disease.
Mitochondrial DNA
In addition to nuclear DNA, the several thousand mitochondria
of each cell possess their own 16.6 kb circular double-stranded
14 The Cellular and Molecular Basis of Inheritance

D loop pattern of inheritance that characterizes many mitochondrial

OH disorders (p. 269).
12S rRNA Cyt b
Transcription
The process whereby genetic information is transmitted from
16S rRNA ND6
DNA to RNA is called transcription. The information stored
Direction of
H-strand replication in the genetic code is transmitted from the DNA of a gene to
ND5 messenger RNA, or mRNA. Every base in the mRNA molecule
is complementary to a corresponding base in the DNA of the
ND1
gene, but with uracil replacing thymine in mRNA. mRNA is
single stranded, being synthesized by the enzyme RNA poly-
merase II, which adds the appropriate complementary ribo-
nucleotide to the 3′ end of the RNA chain.
ND4 In any particular gene, only one DNA strand of the double
ND2
Direction of helix acts as the so-called template strand. The transcribed
L-strand replication ND4L
mRNA molecule is a copy of the complementary strand, or
ND3 what is called the sense strand of the DNA double helix. The
OL template strand is sometimes called the antisense strand. The
COIII
COI particular strand of the DNA double helix used for RNA
COII
ATP6 synthesis appears to differ throughout different regions of the
ATP8
genome.
FIGURE 2.7 The human mitochondrial genome. H is the heavy
strand and L the light strand. RNA Processing
Before the primary mRNA molecule leaves the nucleus
it undergoes a number of modifications, or what is known
DNA, mitochondrial DNA (or mtDNA) (Figure 2.7). The as RNA processing. This involves splicing, capping, and
mtDNA genome is very compact, containing little repetitive polyadenylation.
DNA, and codes for 37 genes, which include two types of
ribosomal RNA, 22 transfer RNAs (p. 16) and 13 protein mRNA Splicing
subunits for enzymes, such as cytochrome b and cytochrome During and after transcription, the noncoding introns in the
oxidase, which are involved in the energy producing oxidative precursor (pre) mRNA are excised, and the noncontiguous
phosphorylation pathways. The genetic code of the mtDNA coding exons are spliced together to form a shorter mature
differs slightly from that of nuclear DNA. mRNA before its transportation to the ribosomes in the cyto-
The mitochondria of the fertilized zygote are inherited plasm for translation. The process is known as mRNA splicing
almost exclusively from the oocyte, leading to the maternal (Figure 2.8). The boundary between the introns and exons

Transcription Transcription
initiation termination

Exon 1 Exon 2 Exon 3

Intron 1 Intron 2 Sense strand
5' TATA box 3'
3' 5'

Translation Translation Poly (A) signal

start stop
Transcription
Polyadenylation
Capping
Primary RNA
Poly (A) tail
5' Cap

Splicing

mRNA

Translation
Post-translational
processing
Protein
FIGURE 2.8 Transcription, post-transcriptional processing, translation, and post-translational processing.
 The Cellular and Molecular Basis of Inheritance 15

consists of a 5′ donor GT dinucleotide and a 3′ acceptor AG
dinucleotide. These, along with surrounding short splicing
consensus sequences, another intronic sequence known as the
branch site, small nuclear RNA (snRNA) molecules and associ-
ated proteins, are necessary for the splicing process.
5′ Capping
The 5′ cap is thought to facilitate transport of the mRNA to
the cytoplasm and attachment to the ribosomes, as well as to
protect the RNA transcript from degradation by endogenous
cellular exonucleases. After 20 to 30 nucleotides have been
transcribed, the nascent mRNA is modified by the addition of
a guanine nucleotide to the 5′ end of the molecule by an
unusual 5′ to 5′ triphosphate linkage. A methyltransferase
enzyme then methylates the N7 position of the guanine, giving
the final 5′ cap.
Polyadenylation
Transcription continues until specific nucleotide sequences are
transcribed that cause the mRNA to be cleaved and RNA
polymerase II to be released from the DNA template. Approxi-
mately 200 adenylate residues—the so-called poly(A) tail—are
added to the mRNA, which facilitates nuclear export and
translation.
Translation
Translation is the transmission of the genetic information from
mRNA to protein. Newly processed mRNA is transported from
the nucleus to the cytoplasm, where it becomes associated with
the ribosomes, which are the site of protein synthesis.
Ribosomes are made up of two different sized subunits, which
consist of four different types of ribosomal RNA (rRNA)
molecules and a large number of ribosomal specific proteins.
Groups of ribosomes associated with the same molecule of
mRNA are referred to as polyribosomes or polysomes. In the
ribosomes, the mRNA forms the template for producing the
specific sequence of amino acids of a particular polypeptide.
Transfer RNA
In the cytoplasm there is another form of RNA called transfer
RNA, or tRNA. The incorporation of amino acids into a
polypeptide chain requires the amino acids to be covalently
bound by reacting with ATP to the specific tRNA molecule by
the activity of the enzyme aminoacyl tRNA synthetase. The
ribosome, with its associated rRNAs, moves along the mRNA,
the amino acids linking up by the formation of peptide bonds
through the action of the enzyme peptidyl transferase to form
a polypeptide chain (Figure 2.9).
Post-translational Modification
Many proteins, before they attain their normal structure or
functional activity, undergo post-translational modification,
which can include chemical modification of amino-acid side
chains (e.g., hydroxylation, methylation), the addition of car-
bohydrate or lipid moieties (e.g., glycosylation), or proteolytic
cleavage of polypeptides (e.g., the conversion of proinsulin to
insulin).
Thus post-translational modification, along with certain
short amino-acid sequences known as localization sequences in
the newly synthesized proteins, results in transport to specific
cellular locations (e.g., the nucleus), or secretion from the cell.

DNA
A A A C T C C A C T T C T T C

U U U G A G G U G A A G A A G

mRNA

Nuclear
membrane

Ribosome

mRNA
(template)
U U U G A G G U G A A G A A G

C U C C A C
A U U C
A U
A U C

tRNA
Glutamic acid Valine Lysine
Phen Lysin
ylalan e
ine
Peptide
FIGURE 2.9 Representation of the way in which genetic information is translated into protein.
16 The Cellular and Molecular Basis of Inheritance

Table 2.1 Genetic Code of the Nuclear and Mitochondrial Genomes

Second Base
First Base U C A G Third Base
U Phenylalanine Serine Tyrosine Cysteine U
Phenylalanine Serine Tyrosine Cysteine C
Leucine Serine Stop Stop (Tryptophan) A
Leucine Serine Stop Tryptophan G
C Leucine Proline Histidine Arginine U
Leucine Proline Histidine Arginine C
Leucine Proline Glutamine Arginine A
Leucine Proline Glutamine Arginine G
A Isoleucine Threonine Asparagine Serine U
Isoleucine Threonine Asparagine Serine C
Isoleucine (Methionine) Threonine Lysine Arginine A
Methionine Threonine Lysine Arginine (Stop) G
G Valine Alanine Aspartic acid Glycine U
Valine Alanine Aspartic acid Glycine C
Valine Alanine Glutamic acid Glycine A
Valine Alanine Glutamic acid Glycine G
Differences in the mitochondrial genetic code are in italics.

The Genetic Code
Twenty different amino acids are found in proteins; as DNA is
composed of four different nitrogenous bases, obviously a
single base cannot specify one amino acid. If two bases were
to specify one amino acid, there would only be 42 or 16 pos-
sible combinations. If, however, three bases specified one
amino acid then the possible number of combinations of the
four bases would be 43 or 64. This is more than enough to
account for all the 20 known amino acids and is known as the
genetic code.
Triplet Codons
The triplet of nucleotide bases in the mRNA that codes for a
particular amino acid is called a codon. Each triplet codon in
sequence codes for a specific amino acid in sequence and so
the genetic code is nonoverlapping. The order of the triplet
codons in a gene is known as the translational reading frame.
However, some amino acids are coded for by more than one
triplet, so the code is said to be degenerate (Table 2.1). Each
tRNA species for a particular amino acid has a specific trinucleo-
tide sequence called the anticodon, which is complementary
to the codon of the mRNA. Although there are 64 codons,
there are only 30 cytoplasmic tRNAs, the anticodons of a
number of the tRNAs recognizing codons that differ at the
position of the third base, with guanine being able to pair with
uracil as well as cytosine. Termination of translation of the
mRNA is signaled by the presence of one of the three stop or
termination codons.
The genetic code of mtDNA differs from that of the nuclear
genome. Eight of the 22 tRNAs are able to recognize codons
that differ only at the third base of the codon, 14 can recognize
pairs of codons that are identical at the first two bases, with
either a purine or pyrimidine for the third base, the other four
codons acting as stop codons (see Table 2.1).
Regulation of Gene Expression
Many cellular processes, and therefore the genes that are
expressed, are common to all cells, for example ribosomal,
chromosomal and cytoskeleton proteins, constituting what are
called the housekeeping genes. Some cells express large
quantities of a specific protein in certain tissues or at specific
times in development, such as hemoglobin in red blood cells
(p. 154). This differential control of gene expression can occur
at a variety of stages.
Control of Transcription
The control of transcription can be affected permanently or
reversibly by a variety of factors, both environmental (e.g.,
hormones) and genetic (cell signaling). This occurs through a
number of different mechanisms that include signaling mole-
cules that bind to regulatory sequences in the DNA known as
response elements, intracellular receptors known as hormone
nuclear receptors, and receptors for specific ligands on the cell
surface involved in the process of signal transduction.
All of these mechanisms ultimately affect transcription
through the binding of the general transcription factors to short
specific DNA promoter elements located within 200 bp 5′ or
upstream of most eukaryotic genes in the so-called core pro-
moter region that leads to activation of RNA polymerase
(Figure 2.10). Promoters can be broadly classed into two types,
TATA box-containing and GC rich. The TATA box, which is
approximately 25 bp upstream of the transcription start site,
is involved in the initiation of transcription at a basal constitu-
tive level and mutations in it can lead to alteration of the
transcription start site. The GC box, which is approximately
80 bp upstream, increases the basal level of transcriptional
activity of the TATA box.
The regulatory elements in the promoter region are said to
be cis-acting, that is, they only affect the expression of the
adjacent gene on the same DNA duplex, whereas the transcrip-
tion factors are said to be trans-acting, acting on both copies
of a gene on each chromosome being synthesized from genes
that are located at a distance. DNA sequences that increase
transcriptional activity, such as the GC and CAAT boxes, are
known as enhancers. There are also negative regulatory ele-
ments or silencers that inhibit transcription. In addition, there
are short sequences of DNA, usually 500 bp to 3 kb in size and
known as boundary elements, which block or inhibit the influ-
ence of regulatory elements of adjacent genes.

Trans-acting GC
elements box
FIGURE 2.10 Diagrammatic representation of the factors that regulate gene expression.
Transcription Factors
A number of genes encode proteins involved in the regulation
of gene expression. They have DNA-binding activity to short
nucleotide sequences, usually mediated through helical protein
motifs, and are known as transcription factors. These gene
regulatory proteins have a transcriptional activation domain and
a DNA-binding domain. There are four types of DNA-binding
domain, the most common being the helix–turn–helix, made
up of two α helices connected by a short chain of amino acids
that make up the ‘turn’. The three other types are the zinc
finger, leucine zipper, or helix–loop–helix motifs, so named as
a result of specific structural features.
Post-transcriptional Control of
Gene Expression
Regulation of expression of most genes occurs at the level of
transcription but can also occur at the levels of RNA process-
ing, RNA transport, mRNA degradation and translation. For
example, the G to A variant at position 20,210 in the 3′
untranslated region of the prothrombin gene increases the
stability of the mRNA transcript, resulting in higher plasma
prothrombin levels.
RNA-Mediated Control of Gene Expression
RNA-mediated silencing was first described in the early 1990s,
but it is only recently that its key role in controlling
post-transcriptional gene expression has been both recognized
and exploited (see Chapter 15). Small interfering RNAs
(siRNAs) were discovered in 1998 and are the effector
molecules of the RNA interference pathway (RNAi). These
short double-stranded RNAs (21 to 23 nucleotides) bind
to mRNAs in a sequence-specific manner and result in their
degradation via a ribonuclease-containing RNA-induced silenc-
ing complex (RISC). MicroRNAs (miRNAs) also bind to
mRNAs in a sequence-specific manner. They can either cause
endonucleolytic cleavage of the mRNA or act by blocking
translation.
Alternative Isoforms
Most (~95%) human genes undergo alternative splicing and
therefore encode more than one protein. Alternative polyad-
enylation generates further diversity. Some genes have more
than one promoter, and these alternative promoters may result
in tissue-specific isoforms. Alternative splicing of exons is also
seen with individual exons present in only some isoforms. The
extent of alternative splicing in humans may be inferred from
the finding that the human genome includes only approximately
20,000 genes, far fewer than the original prediction of more
than 100,000.
The Cellular and Molecular Basis of Inheritance 17
80 bp Transcription
CAAT TATA
start site
box box 25 bp
Transcription
factors
cis-acting enhancers
RNA-Directed DNA Synthesis
The process of the transfer of the genetic information from
DNA to RNA to protein has been called the central dogma. It
was initially believed that genetic information was transferred
only from DNA to RNA and thence translated into protein.
However, there is evidence from the study of certain types of
virus—retroviruses—that genetic information can occasionally
flow in the reverse direction, from RNA to DNA (p. 178). This
is referred to as RNA-directed DNA synthesis. It has been
suggested that regions of DNA in normal cells serve as tem-
plates for the synthesis of RNA, which in turn then acts as a
template for the synthesis of DNA that later becomes inte-
grated into the nuclear DNA of other cells. Homology between
human and retroviral oncogene sequences could reflect this
process (p. 179), which could be an important therapeutic
approach for the treatment of inherited disease in humans.
Mutations
A mutation is defined as a heritable alteration or change in the
genetic material. Mutations drive evolution but can also be
pathogenic. Mutations can arise through exposure to mutagenic
agents (p. 21), but the vast majority occur spontaneously
through errors in DNA replication and repair. Sequence vari-
ants with no obvious effect upon phenotype may be termed
polymorphisms.
Somatic mutations may cause adult-onset disease, such as
cancer, but cannot be transmitted to offspring. A mutation in
gonadal tissue or a gamete can be transmitted to future genera-
tions unless it affects fertility or survival into adulthood.
Harmful alleles of all kinds constitute the so-called genetic load
of the population. There are also rare examples of ‘back muta-
tion’ in patients with recessive disorders. For example, rever-
sion of inherited deleterious mutations has been demonstrated
in phenotypically normal cells present in a small number of
patients with Fanconi anemia.
Types of Mutation
Mutations can range from single base substitutions, through
insertions and deletions of single or multiple bases to loss or
gain of entire chromosomes (Table 2.2). Base substitutions are
most prevalent (Table 2.3) and missense mutations account for
nearly half of all mutations. A standard nomenclature to
describe mutations (Table 2.4) has been agreed on (see http://
varnomen.hgvs.org/). Examples of chromosome abnormalities
are discussed in Chapter 3.
Substitutions
A substitution is the replacement of a single nucleotide by
another. These are the most common type of mutation. If the
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duro mais do 800 rs. (L. J. Ribeiro, Critica do rel. de J. S. Carvalho,
34) Havia, pois, um exagero de dez por cento que, com vinte de
reducção no troco do papel, elevavam a quasi um terço o que
realmente o Estado devedor deixava de pagar aos seus crédores.
Ao mesmo tempo que 16 ou 20 mil contos de propriedade caíam
na posse do Estado, o Thesouro tinha de pedir emprestado o
dinheiro para fazer uma composição com os seus crédores: taes
são as consequencias naturaes das revoluções—têem de
enriquecer os seus sectarios. Os clientes do ministro enriqueciam,
com effeito, por ambos, por todos os modos: engulindo os bens
nacionaes o agiotando com a banca-rota. O decreto de julho, porém,
encarava o problema do restabelecimento da circulação
exclusivamente metalica apenas nas suas relações para com o
Thesouro, não attendendo ás relações contractuaes entre
particulares. A isso veiu occorrer a lei de 1 de setembro, cortando os
embaraços pela raiz, dispondo que todas as obrigações entre
particulares se mantivessem taes-quaes até 38, exprimindo-se d’ahi
por diante as sommas na unica moeda legal, o ouro. A natureza
d’esta disposição, tornando solidarios da banca-rota do Thesouro os
particulares que tinham pactuado n’um regime de circulação mixta—
a fórma da lei em que entrava um papel depreciado—obrigou mais
tarde a reformal-a.

Esse incontestavel serviço da restauração da circulação metalica

era pago á custa de graves sacrificios. A historia dos emprestimos
da dictadura (V. Relat. de Carvalho, 34) era um tecido de confusões
em que a maxima parte dos criticos viam trapaças vergonhosas.
Sem duvida, a emissão de emprestimos durante as epochas
desesperadas da guerra só pôde ser feita á custa de enormes agios;
mas a confusão era tal e tão pequena a confiança na limpeza de
mãos dos procuradores do Thesouro que, invertendo com espirito e
agudeza a locução ordinaria, dizia-se «haver muito quem não
duvidasse da boa fé». (Ribeiro, Critica do rel. etc.)
 Nos primeiros tempos vivera-se dos subsidios do Brazil: 654 mil
libras ou 2:943 contos, mais 437 gastos pela Junta do Porto, mais
cerca de 300 nos Açores: ao todo 3:700 contos effectivos (V. Relat.
Carvalho) com que Palmella e a primeira regencia liberal se tinham
subsidiado a si, aos emigrados e ás varias tentativas e aventuras
mallogradas. Tal fôra a confusão d’esses gastos, que se passou
uma esponja por cima das contas, prescindindo-se d’ellas,
considerando-se tudo approvado. Com D. Pedro entrou em scena
Mendizabal, e, afóra pequenos emprestimos levantados no Porto e
depois em Lisboa, os principaes recursos da guerra vieram dos
emprestimos londrinos. O de dois milhões (23 de setembro de 31)
de 5 por cento liquidou os encargos anteriores:
Devia-se a Marbeley £ 12:600 deram-se-lhe £ 105:600
bonds por
a commissão de » 52:000 titulos no » 150:000
aprestos vendeu por nominal de
negociando-se a 48 por » 837:312 o resto » 1.744:000
» »
Totaes 901:912 nominal » 2.000:000
D’esse producto só as duas primeiras verbas eram porém reaes:
uma por ser divida positiva, outra por ser dinheiro applicado á
compra de armamentos, soldo de mercenarios, etc. O resto
representa-se d’esta fórma:
Juros e outros encargos £ 253:780
atrazados
Commissões e premio da » 295:003
emissão
Dinheiro » 288:529
De sorte que o producto dos dois milhões era realmente
£353:129, a terça parte (ou £606:909 se se lhe juntarem os juros
atrazados) saíndo ao juro annual effectivo de 16 por cento. (Ribeiro,
Critica, etc.)
 O primeiro ensaio não provou feliz, mas o segundo foi ainda peior:
é verdade que as condições tambem tinham peiorado e havia já
muitas esperanças perdidas, mas a politica liberal em materia de
finanças estava conhecida. Que outra cousa podia ser, senão
agiotagem, o systema acclamado pelos bolsistas de Londres? A
emissão de £600:000 (23 de outubro de 32) produzia, liquido de
premios e commissões, £151:925, custando pois a razão de quasi
20 por cento ao anno. Já em Lisboa, depois (14 de setembro de 33),
contratam-se outros dois milhões; e por fim, destinado á conversão
do papel-moeda, um ultimo milhão. Os tres milhões produzem,
ainda captivos de commissões e premios que se encobriam,
£2.356:756, (V. Relatorio, etc.) que não dariam mais de dezoito ou
dezenove centenas de milhares de libras, custando entre 8 e 9 por
cento.
Somma total, a divida externa, que do emprestimo de 1823,
contava um milhão esterlina, subia a quasi sete (6.729:800) ou
29:400 contos da nossa moeda com o encargo annual de 1870.
(Orçamento para 35-6)

Falta-nos vêr agora, para completar o nosso estudo, o estado da

divida interna. A importancia d’ella era em principios de 28: (ap.
Bulhões, Divida port.)
Com Consolidados de 1796 a contos 13:402
juro: 1827
Padrões, a cargo do » 7:000 20:402
Thesouro
Sem Papel-moeda, orçado em » 6:000
juro: Divida fluctuante » 6:490
(atrazados)
Emprestimos diversos » 1:430
Exercicios findos » 4:778 18:698
 Total contos 39:100
Depois da conversão do papel-moeda; depois do decreto (23 de
abril de 35) que converteu em 4 por cento, como juro a metal, a
divida antiga de 6 na forma da lei; liquidada a guerra e
consummadas as bancas-rotas, podemos apreciar o estado em que
se achou o Thesouro: (V. Coll. de Contas da Junta; Ribeiro, Critica e
Bulhões, Div. port.)

Divida reconhecida
Com Emprestimos liberaes dos contos 2:520
juro: Açores, do Porto e de
Lisboa
Titulos de divida antiga » 12:375 14:895
Sem Papel-moeda, por » 3:500
juro: amortisar
Divida fluctuante » 5:689
(atrazados)
Juros por pagar » 897 10:086
Somma contos 24:981

Divida não reconhecida

Legitima: Padrões de juros reaes contos 4:800
Outros emprestimos » 1:670
anteriores
Atrazados de 23-4 » 10:543
Indemnisações » 11:000 28:013
approvadas, por pagar;
e diversos
Illegitima: Emprestimos de D. 4:443
Miguel em 28-30
 Somma contos 32:456
Total » 57:437

O Thesouro, pois, devia em contos 39:100

1828
e confessava dever
em 1835:
por titulos 29:400 »
passados a
extrangeiros
» » nacionaes 25:000 » 54:400
Excesso » 15:300
Deixando de reconhecer » 28:000
creditos legitimos por
Excesso » 43:300
A esta somma devem juntar-se ainda os titulos naturalmente
amortisados pela abolição das corporações possuidoras d’elles.
Quanto a encargos, porém, a situação do Thesouro é diversa: pois a
divida com juro era, em 1828, de 20 mil contos e agora é de 44:300.
Apesar da somma de bens confiscados, o encargo do orçamento
duplíca, embora se não paguem os juros dos padrões, ainda
representantes de um capital de cinco mil contos.

É impossivel dizer que sommas a crise custou á nação, porque se

não medem por numeros as perdas de riqueza e trabalho por todo o
paiz, e menos ainda a perda de gente e de forca, consumidas pela
guerra e pela intriga. Menos se póde contar ainda o valor perdido
das energias gastas em sustos e afflicções!
Póde talvez, porém, calcular-se o que financeiramente se perdeu,
reunindo numeros conhecidos:
 Por parte dos Liberaes
Valor da divida que contrahiram no reino e fóra 27:522
Id. dos subsidios do Brazil, recebidos 2:943
Id. dos atrazados por pagar em 34 4:000
Valor das indemnisações a solver 7:000
Id. das dividas legitimas não reconhecidas 17:013
Id. do terço do papel-moeda, na conversão 2:500
Id. dos confiscos de propriedade inimiga ?

Por parte dos Miguelistas

Valor da divida que contrahiram 4:443
Id. dos vencimentos e juros não pagos durante o seu 8:083
governo
Id. dos dons voluntarios e confiscos ?
Setenta, oitenta, cem mil contos, custou decerto á economia da
nação a guerra que terminára sem conseguir acabar ainda com a
crise, porque á lucta entre o velho e o novo Portugal iam succeder
as luctas dos partidos liberaes. Secco, devastado estava o reino
com os vomitos da cholera, as agonias da fome gemendo por todo
elle: e da mesma fórma o Thesouro, imagem viva do paiz, nú e
vasio, gemia tambem com a lepra da corrupção, da agiotagem, do
puro roubo. O anno de 33-4 dera apenas tres mil contos para uma
despeza de treze mil;[5] e o orçamento de 35-6 apresentava um
deficit de mais de quatro mil,[6] com receitas exageradas.
Começaram a pronunciar-se vivamente os clamores contra a
sociedade Mendizabal-Carvalho e suas combinações em que tantos
lucravam agios, commissões, premios, bonus. Mendizabal furava
pelo meio das bolsas de Paris e Londres, dando luvas aos
Rothschilds, aos Ricardos, aos Foulds, aos Oppenheims, para
pôrem o seu nome nos annuncios das emissões portuguezas. (A
dynastia e a revol. de set. anon.) Carvalho furava pelo meio da selva
das intrigas, como uma estrella caudata de ouro, fechando os olhos:
era dinheiro inglez! O seu processo evitava que a causa se
despopularisasse exigindo impostos, contentava o povo, pagava
tudo em dia, e dava ainda para vencer resistencias que as alfaias
dos conventos e os bens nacionaes não satisfaziam. Era uma chuva
de libras esterlinas: quem viesse depois, que se arranjasse! Não se
podia opprimir o povo, nem ser muito exigente com um
funccionalismo inventado assim, do pé para a mão, para pagar os
serviços á causa. A decima rendia apenas oitocentos contos; e até
1840 nem um dos recebedores geraes nomeados em 34 tinha
prestado contas: uns fugiam, outros escondiam-se; e depois, ainda
em vão o Diario, em 39, publicava a lista dos remissos.
O ministro, indifferente, compassivo, passa-culpas, deixava ir,
considerando que o periodo era transitorio. Afinal, chegára o
momento da desforra: não tinham sido muitos os annos de
amargura? Mas as pretenções da opposição, exigindo limpeza de
mãos ao governo, e ameaçando com essa necessaria banca-rota
onde acabam as viagens de todos os Laws, veio transtornar a
placidez dos dias felizes. Carvalho caiu (27 de maio de 35) e no seu
logar entrou o sincero Campos, mais escrupuloso, menos atilado.
Impellido para além do que a prudencia mandava, o ministro expôz,
em lagrimas, o triste sudario do Thesouro. Chorar é bom;
desacreditar o adversario póde não ser mau; mas que remedio? Diz
o povo que tristezas não pagam dividas. Campos tinha só lagrimas
e invectivas: caiu logo. (15 de julho) O Banco e a agiotagem em
peso exigiam a entrada de Rodrigo e de Silva Carvalho. Saldanha,
na presidencia, que havia de fazer? Deitou ao mar o lastro radical
do gabinete, admittiu os homens habeis em finanças. Estava
imminente a banca-rota: não havia um real, e os da opposição não
mereciam conceito aos argentarios. (Carnota, Memor. of Sald.) O
marechal, entre os dois partidos, com a sua vaidade ingenua, já se
acreditava um arbitro—quasi um rei. Não o tinham convidado para
monarcha no Rio Grande? Não escrevia elle mais tarde, já depois
de ter sido apenas o méro instrumento cabralista, «estou persuadido
que seria um bom chefe n’um Estado qualquer»? (V. carta de 69,
em Carnota, ibid.) Deitou fóra Loulé e Campos; metteu Rodrigo e
Silva Carvalho.
 Via-se que o Law portuguez, liberal em todos os sentidos e para
com todos, era indispensavel. Endividamo-nos: que tem isso? O
futuro a Deus pertence—dizem o turco e o portuguez. Nação de
morgados hypothecados, Portugal sentia-se bem empenhando o
futuro. As dividas cresciam; pagavam-se os juros com dividas
novas; e assim se iam pedindo, consolidando e pagando.—Não é o
que ainda hoje[7] succede?—Só a opposição clamava, e como a
intriga era muita, apezar do fiasco do verão, Campos voltou ao
governo no inverno. (18 de novembro)
Desorientaram-se as cousas e o rival expulso esfregava as mãos
satisfeito: bem o dizia! Utopistas os que pretendiam viver dos
recursos d’uma casa arruinada! Pois não era evidentemente melhor
aproveitar do inglez que nos dava o que lhe pediamos? Era dinheiro
que vinha para cá. Tinhamol-o? Não. Custava muito caro? Deixal-o
custar. Quando não houvesse nada para os juros, não se pagavam:
eis ahi está! Quem perdia? O paiz? não; o inglez. Carvalho, que
assim pensava, não deixava de ter rasão; mas a hypocrisia politica
impedia-lhe que o dissesse. D’ahi provinha o ser batido pelas
sonoras palavras dos adversarios.
Como os factos, porém, o vingaram! A desordem continuava a ser
a mesma, aggravada com a suspensão dos pagamentos. Os
mercenarios clamavam pelos soldos, suspirando por voltar para
casa. Já conformados com a falta das terras promettidas, pediam
apenas um dinheiro que não havia. Davam-se-lhes letras sobre
Inglaterra, e empregados do thesouro, que já tinham aprendido
muito, iam a bordo descontar-lh’as a dez por cento e mais. (Shaw,
Letters) Tudo jogava: a vida era uma sorte. Farrobo fôra cudilhado
pela lei do papel-moeda. Faziam-se e desfaziam-se as riquezas
como nuvens passageiras. Bens de sacristão, cantando vêm,
cantando vão!
O rigido Campos não era homem para tal gente, nem para tal
epocha. Levantava-se contra elle um clamor unanime dos
prestamistas sem juros, dos empregados sem vencimentos, dos
soldados sem pret.—«Em que se parece o sr. Campos com um
cometa? Em ser barbato e caudato. E em que mais? Nos resultados
influentes. O do outro dia deixou-nos o frio, e este a fome».
(Bandeira, Artilheiro, n.º 19) Maldito governo que não paga! «Isso é
falta de paciencia ... O sr. Campos, quando entrou para o thesouro,
que achou lá? Pulgas!» (Ibid.) Mas d’esses bichos, Carvalho fazia
libras, e por isso o foram chamar outra vez. (20 de abril de 36) Era
unico na sua especie.

Comtudo os tempos iam durando, e nada ha peior do que o tempo

para todos os Laws. Se as cousas não andassem! Andavam, porém,
e rapidamente: com aquella velocidade progressiva da machina
capitalista, prolifica por meio dos juros, amortisações,
capitalisações. Dois annos tinham bastado para progredir d’este
modo: (V. Coll. de Contas, 10 de setembro de 36)
1834 1836
Divida 29:400 40:398
externa
capital
» interna 14:895 20:748
»
Somma 44:295 61:146
Accrescimos 16:851
—capital
juros 313
Divida sem
juro:
Papel 3:500 3:115
moeda
Diversos 6:586 6:852
Encargos juros 2:334
totaes da
divida:
 amort. 627
Divida
mansa
(Padrões, 17:013
atrazados,
etc.)
E n’esses dois annos decorridos, estava consumido, além do
mais, o melhor dos bens nacionaes. Ardia tudo n’um fervor de
appetite que já para muitos começava a infundir receios de uma
indigestão tremenda. Dois annos de paz tinham custado quasi tanto
como seis annos de guerra: muito mais, se se contar o que o
Thesouro não pagou. A guerra fôra cara, mas a victoria era ruinosa.
No meiado do verão (14 de julho de 36) pegou fogo no thesouro. Já
tudo ardia, lá dentro d’esse palacio onde á inquisição religiosa
succedera a inquisição agiota, com as suas tenazes de papel
timbrado, os seus troncos de juros, retornos, commissões, premios;
com a sua algaravia bancaria, herdeira do historico latim das
sentenças singulares ... Qual dos desvarios dos homens valerá
mais?
Ardeu em verdadeiro lume o Thesouro em julho; mas já vinha
ardendo havia muito em lepra que o roía de torpezas, e n’um vasio
que o amargurava de contracções, como as dos estomagos
famintos. O povo dizia que o fogo fôra posto, para saldar muitas
contas; mas o ministro, Pombal da moderna finança, Law portuguez,
iniciador da nação nova nos segredos do capitalismo; o ministro,
como o velho marquez no seu terramoto, mandou pagar o semestre
no dia seguinte. Ardia o Thesouro? Agua ao fogo, e paguem!—
traducção do «enterrar dos mortos e curar dos vivos». Ardia o
Thesouro! Boas, francas labaredas, impellidas por uma ventania
fresca, subiam crepitantes, levantando no ar os farrapos da
papelada. Durou doze horas o incendio, do meio-dia á meia noite.
Muitas horas mais, muitos dias, bastantes annos, ia durar outro
incendio, acceso pelas ambições mal soffridas, pelas illusões
crentes, pelo protesto contra o systema da veniaga e da
delapidação, contra o regabofe que a uns enchia de coleras e a
muitos mais de invejas. Tambem tinham soffrido: tambem queriam
gozar!
Em julho ardeu o Thesouro; em setembro rebentou a revolução.

4.—A FAMILIA DOS POLITICOS

Mas antes de setembro e da nova face que as cousas tomam

n’essa data, falta-nos ainda estudar mais de um dos lados da nação,
no seu primeiro periodo liberal ...
Além das causas anteriores conhecidas, a propria victoria do novo
regime concorria mais ainda para que Portugal fosse uma nação de
empregados publicos. A suppressão dos conventos, o resfriamento
dos sentimentos religiosos, diminuiam a offerta e tambem a procura
de lugares na Egreja. As causas economicas anteriores já tinham,
póde dizer-se, supprimido a navegação; as tentativas industriaes
manufactureiras do marquez de Pombal não tinham vingado; e a
recente crise de oito annos, rematada por um terramoto das velhas
instituições sociaes, viera talar os campos, arruinar a agricultura.
Portugal achava-se, pois, forçado a substituir por um communismo
burocratico o extincto communismo monastico. Durante a guerra, a
nação fôra um exercito; agora, licenceadas as tropas e supprimidos
os soldos, de que viveriam os soldados? É verdade que o governo
podia ter feito como se fazia outr’ora em Roma; mas a distribuição
das terras conquistadas não podia ter lugar, porque os capitães
queriam-n’as para si, por grosso. Força era portanto optar por outra
saída: e qual, senão os empregos publicos?
Por sobre esta necessidade social appareciam as necessidades
politicas. Em que peze ás seccas affirmações doutrinarias e ás
chimeras dos philosophos, todas as nações consistem realmente na
aggregação de clientelas para as quaes um chefe é ao mesmo
tempo um instrumento, um representante e um defensor. Essa
primeira fórma da sociedade romana exprimia uma verdade natural
que os systemas encobrem mal.[8] Quando, mais tarde, se imagina
subordinar a doutrinas abstractas a existencia dos povos, observa-
se que os factos naturaes espontaneos, reagindo, tiram a realidade
ás formulas. Assim, nas velhas monarchias havia chefes e partidos,
cujo poder era maior do que o do rei; assim, nos governos
formalistas liberaes, o poder pessoal dos chefes politicos, apoiado
sobre instrumentos como as eleições, a imprensa, etc., é a força
positiva que impera sophismando uma constituição, a qual os chefes
confessam e dizem respeitar por um sentimento de conveniencia e
de pudor publico, mais ou menos consciente.
Quando a machina social se desorganisa, apparecendo o que se
chama revolução ou crise, vêem-se mais ao vivo como as cousas
são na realidade. Era isto o que succedia entre nós, nos tempos que
agora atravessamos. Constituiam-se as clientelas; e como a
sociedade era ainda quasi um acampamento assente sobre um
territorio desolado; como não havia outros meios de vida patentes a
numerosas classes desorganisadas, essas clientelas eram o que
podiam ser: burocraticas e militares.
«Para um homem ser ministro de Estado basta que um batalhão,
de mãos dadas com um periodico, o queiram». (Bandeira, Artilheiro,
n.º 25) Sociedades como a portugueza, lançadas de chofre n’uma
vida nova, sem precedentes nem raizes na historia immediata;
povos de um temperamento violento ou ardente, sem instrucção
nem riqueza: estão condemnados a um revolvêr desordenado, em
que idéas, ou falsas ou mal concebidas, se combinam com os
instinctos intimos que a anarchia traz á flôr da realidade. Entre os
debates de doutrinas extravagantes e as luctas dos bandos
armados, vae pouco a pouco effectuando-se, de um modo
naturalistamente espontaneo, a reconstituição do corpo social
desorganisado. É como quando o furacão levanta e ennovela o pó
das estradas que se agita, mistura-se, e gradualmente vae outra vez
assentando.
Nada nos deve pois admirar o que succedeu em Portugal:
outrotanto succede ainda hoje á Grecia e aos paizes do Oriente
slavo; e o mesmo que nos aconteceu a nós, foi o que se deu na
Italia e na visinha Hespanha. Os homens da Europa central,
francezes, inglezes, allemães, belgas, filhos de sociedades
differentes, não podiam comprehender, nem o nosso bandidismo,
nem o systema das nossas clientelas ou partidos, nem o nosso
communismo burocratico, nem a nossa furia politica, paixão
dominante que a occasião, o interesse, e a doutrina da anarchia
individualista concorriam para fomentar. D’esta incomprehensão do
caracter da sociedade pelos extrangeiros que mandavam n’um paço
occupado por uma rainha quasi extrangeira, veiu a principal causa
das reacções e revoluções que alagaram o paiz em sangue,
consummando a obra de uma ruina já avançada. Dir-se-ha porém
que, se tal motivo não surgisse, a vida portugueza de 34 a 51 teria
sido uma paz? Não, nunca. Haveria apenas um elemento menos de
guerra. Os diversos bandos, com seus chefes e clientes, seus
principios e interesses, seus programmas e guerrilhas, teriam
combatido da mesma fórma entre si, até que o cansaço universal
impuzesse uma paz que nenhuma clientela podia impôr com a
victoria, por falta de força bastante para a ganhar.

O motivo de uma tal fraqueza está nas condições necessarias de

uma sociedade no caso da nossa. Os debates e as luctas dão-se
entre a minoria minima dos politicos, advogados ou militares, com
discursos ou correrias, formulas ou guerrilhas.
Esta qualidade de homens é quasi a unica que se interessa
nos negocios publicos; occupando todos os cargos da
administração, constitue o que chamam opinião, domina as
eleições e toma assento nas côrtes. D’ella se compõem os
poderes executivo e legislativo, sendo ao mesmo tempo
governo e povo. O numero d’estes politicos não é
consideravel, mas é demasiado relativamente ao magro
orçamento de Portugal. (Lasterie, Portugal etc., na Revue des
deux mond. 1841)
«Cada governamental, dizia o conde da Taipa, é um artigo da
carta.» E se, com effeito, o orçamento era magro de mais para
sustentar os politicos; se o communismo burocratico era bem mais
difficil de manter do que o monastico, pois os pedintes não se
contentavam com o caldo e a brôa das portarias: é tambem facto
que os homens de alguma cousa haviam de comer. E se não havia
outra occupação para onde se voltassem?

Uma nação de empregados

É Portugal? Certamente.
Até D. Miguel do throno
De D. Maria é pretendente.

(Bandeira, Artilheiro, n. 22).

Não podia ser de outro modo, e já vimos o porquê. Mas o
orçamento era magro, magrissimo: se se pagava, honra seja á arte
do nosso Law, que achára em Mendizabal um corretor e em Londres
uma colonia excellente para a lavra das minas de libras. Comtudo
essas fortunas sempre duram pouco; e o Thesouro soffria de
intermittentes, com os ataques de escrupulo da opposição. Os
pobres empregados viam-se n’uma situação triste: «Em que se
parecem com os papa-moscas? Em que estão todos com a bocca
aberta». (Ibid. 31)
Se é verdade que quem «ataca o governo não saiu despachado»;
(Ibid. 8) não é menos verdade, comtudo, que seria injusto vêr na
constituição da familia politica o mobil exclusivo da fome ou da
cubiça. Outros motivos, não menos graves, concorriam para a
formação das gentes o para as rivalidades e luctas dos chefes e
clientes. «Nunca póde haver ministros bons; e porque? Porque os
ministros são seis e os pretendentes seis mil». (Ibid. 28) Nas velhas
sociedades patriarchaes ou feudaes, a tradição e a lei mantinham o
lugar de cada um; mas agora as fórmas de authoridade natural
surgiam do seio da anarchia positiva, e a doutrina da anarchia
individualista e da concorrencia livre de todos a tudo, consagrava a
ambição do mando com a authoridade de uma theoria.
A ambição, eis ahi, pois, o principal dos motivos pessoaes,
superior ainda á cubiça e á fome, cujo papel é mais anonymo e
collectivo, mais talvez dos clientes do que dos patrões. A franqueza
com que todas as portas se abriam a toda a gente; a segurança com
que todo o «individuo» por soberano, se achava apto para tudo; o
systema, que destruira a administração especialisada nas antigas
juntas e conselhos, e confiava a solução de todos os negocios ás
assembléas saídas do cháos da eleição; a victoria que «deitára tudo
abaixo» e enchia de orgulhos os demolidores: tudo concorria para
inchar as vaidades e aquecer as ambições. Pullulavam os homens-
novos, soletrando Volney e Mirabeau, Dupuy, Rousseau e o Citator,
cheios de affirmações, philaucia, e desprezo desdenhoso pelo
antigo saber fradesco. E ao lado dos pedantes, havia por todo o
reino os ingenuos, cheios de crenças quasi religiosas n’um
Evangelho novo. A camara de Ribaldeira escrevia assim a Passos
Manuel:
Não somos doutrinarios nem aristocratas; muito presamos
Montesquieu, mas não é só elle que fórma a nossa propria
bibliotheca; desde Hobbes até Rousseau, desde Machiavelli
até Batham (sic) algües outros temos lido; em nossas aldeas
tambem consultamos a Historia dos Washingtons, dos
Triunvirs (!) dos Neros, etc., etc. (Off. de 20 de dez. autogr. na
corr. dos Passos)
Os jornaes diziam tudo, conheciam todas as questões, resolviam
todos os problemas, porque nada ha mais atrevido do que a
ignorancia. E sentados sobre as ruinas da patria assolada, cuspiam-
lhe em cima, com desprezo, renegando-lhe a historia, com as
cabecinhas empertigadas e occas voltadas para a França,
acclamada em phrases banalmente pomposas. A emigração
educára-os, e voltavam «enfatuados de sábia», escarnecendo dos
goticos, infelizes que nunca tinham saido de Portugal.
Muitos se julgavam sabios por aprender um cumprimento
em francez, misturando de vez em quando um good night
seguido de uma pirueta; por aprender meia duzia de nomes
de autores, usar de charuto, alugar uma cara de tolo, raspar-
lhe a vergonha, namorar a torto e a direito, entrar nos
botequins, lêr por desfastio, fallar de politica e de não sei que
contracto, metter a religião a ridiculo. (Bandeira, Art. 23).
 Tudo era necessario e natural, embora seja indubitavelmente
grutesco. A pretensão de que a liberdade era a formula absoluta, o
systema a verdade revelada e a historia uma peta; a pretensão da
infallibilidade da razão individual e da soberania das vontades
humanas, tinham de forçosamente trazer os costumes a um estado
que corresponde aos outros lados da physionomia social. A anarchia
na escola era, e não podia deixar de ser, a anarchia na realidade; e
a negação systematica da authoridade collectiva e do caracter
organico da sociedade, depois de condemnar a historia,
condemnava a actualidade, valendo-se dos abundantes documentos
que ella lhe fornecia. Tudo era peta, burla, infamia:
Em que consiste o direito de votar? É o direito banal pelo
qual eu sou obrigado a conduzir um papel de que não faço
caso ...
Que são os grandes, os chefes, junto ao throno? São
canos reaes por onde se despeja toda a immundicie da alma
dos seus protectores; delegados á latere do vicio, vendem os
interesses do povo por um crachá, fazem e desfazem
ministerios com a mesma sem-ceremonia com que despejam
o regio ourinol ...
Leilões de generos avariados: Boa-fé no largo das
Necessidades; Egualdade de Direitos nas secretarias
d’Estado; Liberdade de voto, nas assembléas eleitoraes, etc.
(Bandeira, Artilheiro, n. 2 e 23).
Com effeito, os chefes não se tornavam crédores de um respeito
demasiado.
Á morte de D. Pedro, segundo vimos, Palmella apoderou-se do
governo, fundindo-se a sua clientela, ou partido, com o da regencia
n’esse momento acabada. O caracter revolucionario do governo da
dictadura terminára, e dos antigos ficavam no ministerio apenas
Freire, e Carvalho o financeiro indispensavel. Era necessario pôr
ponto no «deitar abaixo». Já Palmella, no conselho de Estado, tinha
votado com a maioria contra a extincção dos conventos, que apezar
d’isso Aguiar decretou em secreto accôrdo com D. Pedro; já pozera
depois o seu veto ao remate do plano de Mousinho, a abolição dos
morgados. Moderado sempre e aristocrata, o radicalismo dos
philosophos parecia-lhe tão mau como a demagogia: quer a vencida
demagogia miguelista, quer a demagogia ameaçadora da opposição
radical. Com os olhos invariavelmente voltados para a Inglaterra,
não concebia outro typo de nação, além do typo aristocratico, liberal
e conservador. No governo succedia-lhe agora o que sempre lhe
succedera: era antipathico e ninguem o recebia. Reconhecendo
todos a sua habilidade, parecia a todos que só a ambição pessoal o
movia. O povo, já minado pelas theorias democraticas, considerava-
o um tyranno; e a cauda dos odios pessoaes que as intrigas e os
erros da emigração lhe tinham feito, voltava-se agora e mordia-o.
Quando pela terceira vez a carta se rasgou para casar (1 de
dezembro de 34) a rainha com o primeiro dos seus dois maridos
allemães, quando a opposição pedia «um fidalgo portuguez»,
dissera-se muito que Palmella pensava em fazer da rainha sua nora.
Mas esse principe contratado para dar herdeiros á corôa
portugueza (os nossos visinhos hespanhoes chamam coburgos a
taes maridos) durou pouco; e a sua morte (28 de março de 35) foi
motivo de uma crise. Lisboa appareceu crivada do pasquins
accusando Palmella de envenenador, o attribuindo-lhe a ambição de
querer para seu filho a mão da rainha: Wellington, de lá, apoiava o
plano! O povo acreditou e saíu. Houve tumultos graves (29),
pedindo-se a cabeça do traidor. Terceira que já em 27, nas
Archotadas, carregara essa canalha desembainhou outra vez a
espada fiel e manteve a ordem.
Mas só uma ordem apparente, porque no fundo havia uma
anarchia real. Varias clientelas, com os seus chefes e os seus
programmas varios, ambicionavam o poder. Palmella era um estorvo
e contra elle se fundiam as opposições todas, congregadas para o
ataque.

Um pasteleiro queria
Fabricar um pastelão
E porque tinha de nada
 Deu-lhe o nome de fusão

Arde o forno, o pastel dentro

Principia a fermentar
Entornou-se; perde a massa:
Só ficou o alguidar.

(Bandeira, Artilh. 12 set.)

Esse alguidar era Saldanha, que nunca pareceu mais vasio, mais
de barro, que agora. O rival tinha um pensamento, elle apenas um
nome. Palmella dispunha de uma clientela firme; Saldanha, já
desacreditado perante os radicaes, embora ainda representasse o
papel de seu chefe, era um general sem exercito, condemnado a
presidir a um gabinete mixto. Esturrou-se logo o pastel, e o alguidar
appareceu transbordando de gente radical: um ministerio puro de
opposição. (Sá, Loulé, Caldeira, Campos, 25 de nov.)
Varios tempos, licções eloquentes, arrependimentos já tardios,
enchiam a cabeça de Saldanha, lembrando-se do papel que fizera
em 26-7, das cousas que authorisara com o seu nome em Paris.
Achara-se levado por um ardor de gloria nas azas da revolução, e
não tivera podido medir bem o destino d’esse vôo. Já de ha muito
que reconsiderara. O leitor lembra-se dos episodios do Cartaxo.
Mas, sem o talento do rival, que ficaria sendo, se deixasse de ser o
chefe de um radicalismo já então por elle renegado? Uma espada
apenas, prompta sempre a obedecer e incapaz de mandar, como
Terceira? Não: isso não podia admittil-o a sua vaidade. Seria descer
muito. Mas para não descer—elle provavelmente já nem queria
subir mais—era impossivel ficar immovel. O partido de que se dizia
chefe, tinha-o apenas como um rotulo, um pendão, sem dar a
minima importancia ás suas vontades ou desejos pessoaes. Seguia
o seu caminho, guiado por outros; e para que Saldanha, agora no
governo, não fosse francamente renegado, era mistér que saísse da
inacção e se declarasse o dictador que Passos foi no anno seguinte.
Já em 27 succedera o mesmo, e lembrava esse episodio: quando
faltava apenas extender o braço e sagrar-se chefe da revolução,
Saldanha, tendo-a acompanhado até ahi, parava, tremia com
escrupulos, fugindo.
Depois do Cartaxo quizera, como dissemos, remir os erros da
emigração, encostado-se ao cartismo (Hontem, hoje e amanhan, op.
anon.); mas os cartistas que lhe pagariam bem e usariam com
prazer da sua espada, como faziam á de Terceira, não lhe davam
importancia ás opiniões nem o reconheceriam chefe. Por seu lado
os radicaes, vendo a fraqueza inconsistente d’esse chefe theatral,
sem repellirem o instrumento que ainda lhes servia, já se
esforçavam por mostrar bem claro que lhe não obedeciam. Nas
eleições de 34, Saldanha acompanhara D. Pedro ao Porto. Ia n’uma
posição singular, para convencer o principe do poder do seu partido,
dando por tal fórma um grande peso á sua adhesão ao throno. D.
Pedro, por seu lado, levava por fim bater no Porto, com a presença
do marechal, a influencia do radicalismo dirigido pelos irmãos
Passos; e com Saldanha á mão, Saldanha que lhe asseguraria a
obediencia dos que ainda talvez suppozesse seus clientes,
esperava tudo da conversão do caudilho militar ás opiniões
conservadoras. (Macedo, Traços.)
Os chefes enthusiastas e fortes do futuro Setembrismo deram
uma licção ao principe e ao seu acolyto. Saldanha, candidato, foi
batido no primeiro escrutinio da eleição: onde estava o seu poder?
Mas para dizer a D. Pedro que a victoria lhe não pertencia, e para
dizer ao general que apesar do seu procedimento o não renegavam,
usando de uma magnanimidade que talvez o desviasse do tortuoso
caminho que seguia, elegeram-no no segundo escrutinio. (Macedo,
Traços) Era uma victoria mortal, uma estocada em cheio no inchado
balão das esperanças dos dois viajantes. Tornaram ambos a Lisboa
corridos.
Saldanha, apesar de tudo, ainda foi sentar-se no ultimo e mais
elevado banco da esquerda da camara. Illudir-se-hia ainda com a
boa figura que fazia de lá a sua presença nobre e pomposa? Talvez;
porque se tinha ingenuamente n’uma grande conta, e dava ouvidos
abertos á adulação. (Hontem, hoje e am.) Quando Palmella teve de
cahir, o chefe natural do governo era Saldanha: mas, como já vimos,
a sua falsa posição creou um pastel mixto pouco duradouro; (4 de
maio a 18 de nov.) e a entrada do seu partido obrigou-o a elle a
sahir, (25 de nov.) corrido, desacreditado e renegado. Pagava o
devido preço da sua politica dubia: via fugir-lhe toda a clientela; era
um homem perdido e abandonado pelos que tinham sido os seus e
o apeavam definitivamente de um throno que durara oito ou nove
annos. Retirou para Cintra a ensaiar lavouras. (Carnota, Mem.)
Não foi a queda d’esse chefe que pouco podia e já nada queria
fazer, foi a impotencia da nova clientela exaltada quem a precipitou
do governo (19 de abril de 36). Voltou a antiga gente, menos
Palmella que tambem no isolamento remia velhas culpas. Os dois
próceres rivaes, por tanto tempo inimigos poderosos, achavam-se
egualmente reduzidos a nada, agora que já se entendiam, depois de
feitas as pazes. Havia um outro duque, sem idéas politicas á
maneira do diplomata, sem fogachos de ambição e rompantes de
soldado á maneira de Saldanha; um outro duque, boa pessoa,
politicamente nulla e por isso sempre fiel, excellente individuo para
pôr á frente de um governo onde a antiga gente (Freire, Aguiar,
Carvalho) restaurada queria começar uma vida nova, pensando
soffrear com o utilitarismo e uma administração energicamente
pratica, o torvelino de confusões politicas, de ambições pessoaes.
Seria outra dictadura. Mas onde estava D. Pedro? Terceira presidiu
a esse ministerio que a revolução de setembro derrubou,
encerrando o primeiro periodo da vida liberal portugueza.
Afflicto pelos pedintes, pois da sua clientela antiga só os
mendigos restavam fieis, despeitado, ferido no seu orgulho,
prejudicado nos seus interesses, Saldanha via-se na falsa posição
de não poder ser cousa nenhuma. Para o governo, vivamente
atacado e decidido a dissolver as camaras, o general buliçoso e
ávido, era, porém, a ameaça viva de uma revolta militar. Accusaram-
n’o os seus amigos de outr’ora de se ter vendido n’esta occasião:
«desde aquella epocha, de deserções em deserções, chegou á
situação em que hoje (1854) está, desprezado por todos os partidos:
porque se algum ainda lhe faz festa não é porque o estime, é por
ser um tronco velho, sobre que ainda alguem se sustenta».
(Liberato, Mem.)